Microvillus inclusion disease

MVID is characterized by severe, large amounts of watery diarrhea appearing at birth or within seventy-two hours. Symptoms of a rare late onset form may not occur until two or three months after birth. Diarrhea persists even after oral feeding is stopped and does not decrease with age. Diarrhea often worsens after feeding because of malabsorption of necessary nutrients. The diarrhea often results in life-threatening complications, specifically severe dehydration and metabolic acidosis, which may cause kidney failure, requiring the infant to be hospitalized. There may also be related weight loss, growth retardation and developmental delay.

MVID is caused by loss of function changes (mutations) in myosin Vb (Myo5b) gene, a molecular motor gene that is responsible for traffic of proteins into the brush border of epithelial cells. Most cases of MVID are caused by mutations in Myo5b. However, some patients with MVID with late presentation and milder disease have been reported to have mutations in syntaxin 3, a gene for a SNARE protein that is responsible for vesicle fusion with the membrane.

Fewer than 100 cases of MVID have been reported in the medical literature. The true prevalence of this disorder is unknown. Most cases become apparent soon after birth, but it is also believed by some that there is a later-onset form that becomes apparent six to eight weeks after birth in infants that, until then, have appeared healthy. MVID affects more females than males with a sex ratio of about 2:1.

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

Lactose intolerance is a malabsorption syndrome that results from impaired absorption of a sugar found in milk (lactose). This nutrient is normally absorbed in the small bowel. Lactose intolerance is characterized by diarrhea and abdominal distention causing stomach pain and gas (flatulence) that occurs after drinking milk. A lack of one or more intestinal enzymes results in an inability to digest certain carbohydrates. Lactase, maltase, isomaltase, and sucrase usually split complex sugars into simple sugars. In patients with lactose intolerance, the enzyme, lactase, which digests this sugar in the small bowel, is lacking. Patients with MVID also display carbohydrate malabsorption because of lack of development of the intestinal brush border.


Mikulicz Syndrome

IgG4相关性泪腺和唾液腺炎

Mikulicz syndrome is a chronic condition characterized by the abnormal enlargement of glands in the head and neck, including those near the ears (parotids) and those around the eyes (lacrimal) and mouth (salivary). The tonsils and other glands in the soft tissue of the face and neck may also be involved. Although the disorder is almost always described as benign, it always occurs in association with another underlying disorder such as tuberculosis, leukemia, syphilis, Hodgkin’s disease, lymphosarcoma, Sjögren syndrome, or lupus (SLE). People who have Mikulicz syndrome are at heightened risk for developing lymphomas.

Mikulicz syndrome is characterized by the sudden onset of extreme dryness in the mouth (xerostomia) that may lead to difficulty swallowing and tooth decay.  Other symptoms include enlarged tear glands (lacrimal glands), leading to absent or decreased tears; enlarged glands in the neck (parotid glands); hard, painless swellings (tumefactions) of the saliva glands (salivary glands) of the mouth and those near the ears (parotid).   Glands near the jaw (submaxillary) may also become swollen.  Symptoms may persist for long periods of time or come and go with frequent recurrences. The symptoms of Mikulicz syndrome are very similar to those of Sjögren syndrome and some researchers suspect that they may be the same disorder (see Related Disorders section of this report).

The exact cause of Mikulicz syndrome is not known, although it is suspected to be an autoimmune disorder.  Autoimmune disorders are caused when the body’s natural defenses against foreign or invading organisms (e.g., antibodies) begin to attack healthy tissue for unknown reasons.

Mikulicz syndrome affects more females than males and most often presents during the middle adult years.

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

Mumps is an acute viral illness that causes painful inflammation and swelling of the salivary glands, including the parotid, submaxillary, sublingual, and buccal glands.  At one time, Mumps was a common infectious disease of childhood.  However, a vaccine against this disease was developed in 1967.  The onset of the illness is marked by headache, loss of appetite, a general feeling of ill health (malaise), and a low to moderate fever.  Within 24 hours, the temperature rises to approximately 104.0F and is usually associated with pain and swelling of the glands in front of the ears (parotid) and under the jaw (submaxillary).  (For more information on this disorder, choose Mumps as your search term in the Rare Disease Database.)

Biopsy of one of the swollen glands is key to the diagnosis of Mikulicz syndrome. An ultrasound examination of the area may help to rule out other reasons for gland swelling. Treatment of this disorder is symptomatic. Medical therapies are more productively directed toward the treatment of any underlying disease. Artificial tears may be used to maintain moisture in the eyes, and artificial saliva may be used to treat oral symptoms.


Marfan syndrome

MFS is an autoimmune disease in which antibodies against a bacterial or viral infection cross-react with and attack the nerves. The site of attack may be the myelin sheaths, which insulate and protect the nerve fibers (axons) or the axons themselves. The principal autoantibody is directed against a molecule called ganglioside GQ1b, which is especially present on the nerves affected. The antibody is present in the blood of at least 80% of people with MFS and can be used to confirm the diagnosis.

MFS is rare, affecting only one to two people per million each year in most parts of the world and is more common in East Asia. MFM affects children and adults, is more common in males than females and in the young than the old. The average age of onset is 45 years.

Rarely, patients only have single components of MFS such as ophthalmoplegia (paralysis of eye movements) or ataxia (incoordination). MFS can progress to involve the limb and respiratory muscles, and this is called the MFS-GBS overlap syndrome. Researchers have not yet found a way to predict which patients will progress from MFS into more severe disease, but in one series progression always occurred during the first week.

MFS is often hard to diagnose because it is rare and can mimic other neurologic diseases such as myasthenia gravis, botulism, diphtheria, brain stem stroke, brain stem encephalitis and basal meningitis. Physicians should have a high index of suspension, rule out similar diseases and consider testing for anti-GQ1b antibody to help diagnose Miller Fisher syndrome.


Postaxial acrofacial dysostosis

The specific symptoms associated with Miller syndrome may vary from one person to another. Affected individuals may develop a variety of craniofacial and limb abnormalities. Most abnormalities are noticeable at birth.

Miller syndrome is caused by mutations in the dihydroorotate dehydrogenase (DHODH) 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.

Miller syndrome is a rare disorder with an estimated prevalence of approximately 1 case per 1 million newborns. Because cases may go undiagnosed or misdiagnosed, determining the true frequency in the general population is difficult. Fewer than 75 cases have been described in the medical literature. Males and females are affected in equal numbers.

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

A diagnosis of Miller syndrome is based upon a thorough clinical evaluation, a detailed patient history, and identification of characteristic physical findings. Many of the associated abnormalities are present at birth (congenital).


Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare multisystem disorder characterized by progressive degeneration of the muscles of the gastrointestinal tract causing gastrointestinal dysmotility, weakness of extra-ocular muscles causing drooping of the eyelids (ptosis) and restricted eye movements (ophthalmoparesis), degeneration of peripheral nerves causing altered sensation and weakness the distal arms and legs, and general wasting (cachexia). The specific symptoms associated with MNGIE vary from case to case and may include vomiting, nausea, diarrhea, abdominal pain, and numbness or sensations of pins and needles in the hands and feet. . Additional findings may occur in some cases. MNGIE is caused by changes (mutations) in the TYMP gene encoding thymidine phosphorylase (TP) and is inherited as an autosomal recessive trait.

The symptoms and severity of MNGIE vary from case to case. Onset of symptoms is usually before 20 years of age, but may range from 5-60 years of age. MNGIE is characterized by a variety of gastrointestinal and neurological findings.

MNGIE 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.

MNGIE is an extremely rare disorder that affects males and females in equal numbers. The prevalence is unknown and as of 2011 fewer than 200 cases have been reported in the medical literature. Researchers believe that the disorder often goes unrecognized or misdiagnosed, making it difficult to determine its true frequency in the general population.

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

A diagnosis of MNGIE is suspected based upon a detailed patient history, a thorough clinical evaluation, identification of characteristic findings, and a variety of specialized tests such as blood tests or magnetic resonance imaging (MRI). Blood tests may reveal elevated lactic acid. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. In individuals with MNGIE, it is used to demonstrate asymptomatic leukoencephalopathy.


Mitral Valve Prolapse Syndrome

性腺功能减退-二尖瓣脱垂-智力障碍综合征

The mitral valve is the valve between the left upper and left lower chambers (left atrium and left ventricle) of the heart. Mitral valve prolapse syndrome (MVP) is a common condition in which one or both of the flaps (cusps) of the mitral valve bulge or collapse backward (prolapse) into the left atrium during ventricular contraction (systole). In some cases, this may allow leakage or the backward flow of blood from the left ventricle back into the left atrium (mitral regurgitation).

In many individuals with mitral valve prolapse syndrome (MVP), no symptoms are apparent (asymptomatic) and the condition is often nonprogressive.  However, others with MVP may develop fatigue, difficulty breathing (dyspnea) with exertion, awareness of the heart beat and a pounding or racing of the heart (palpitations), and abnormal heart rhythms (arrhythmias).  Additional signs may include lightheadedness, fainting episodes (syncope), abnormally low blood pressure upon standing (orthostatic hypotension), headaches, chest pain, and/or other symptoms and findings.

The specific underlying mechanism responsible for mitral valve prolapse syndrome (MVP) is unknown.  However, evidence indicates that various changes of the mitral valve or the lower left chamber of the heart (left ventricle) may lead to MVP.  Such abnormalities may include excessive or redundant mitral valve flap (cusp) tissue and/or elongation of the strands of tendon (chordae tendinea) that anchor the cusps to certain muscles (papillary muscles) of the ventricle.

Although mitral valve prolapse syndrome (MVP) has been reported in individuals of various ages, it is most commonly noted in young adults.  Estimates indicate that MVP affects approximately four to eight percent of young adults in the general population, with females affected more commonly than males.

As noted above, mitral valve prolapse syndrome may occur as an isolated condition or in association with various underlying disorders or syndromes.  For further information, please see the Causes section above or use the disease name in question as your search term in the Rare Disease Database.

Mitral valve prolapse syndrome (MVP) may be diagnosed based upon thorough clinical examination, a complete patient and family history, and various tests. The condition is often recognized through use of a stethoscope during routine physical examination, based upon detection of a characteristic clicking sound or sounds (systolic clicks) and/or a subsequent, delayed, high-pitched murmur (late systolic regurgitation murmur). The diagnosis may be confirmed based upon specialized imaging techniques, particularly echocardiography, during which sound waves are directed toward the heart, enabling physicians to identify abnormal positioning and prolapse of the mitral valve flaps. In some cases, additional cardiac and other diagnostic studies may be recommended to help confirm and assess the severity of potentially associated abnormalities, such as accompanying regurgitation.


Mixed connective tissue disease

Mixed connective tissue disease (MTCD) is an uncommon systemic inflammatory rheumatic condition. MCTD is a specific subset of the broader category of rheumatic overlap syndromes, a term used to describe when a patient has features of more than one classic inflammatory rheumatic disease. These classic rheumatic diseases include systemic lupus erythematosus, polymyositis, scleroderma and rheumatoid arthritis. Individuals with an overlap syndrome may, but need not meet, complete diagnostic criteria for one (or more than one) classic rheumatic disease. MCTD is distinguished from other overlap syndromes by a laboratory result: MCTD patients have rheumatic overlap syndrome plus anti-RNP antibodies. Additionally, it has been proposed that the term MCTD be reserved for patients with clinical features that include at least one of the following common manifestations: Raynaud’s phenomenon, puffy fingers or swollen hands.

Individuals with MCTD have symptoms that overlap with those of two or more inflammatory rheumatic diseases. These diseases, in which autoimmunity, excess immune activation and inflammation are hallmarks, include systemic lupus erythematosus, polymyositis, scleroderma and rheumatoid arthritis. (For more information on these disorders, see the Related Disorders section of this report.) While inflammatory rheumatic diseases have at times been referred to as connective tissue diseases, this can cause confusion with other conditions which are characterized by biochemically abnormal connective tissues (such as Ehlers-Danlos syndrome or Marfan syndrome) in which autoimmunity, excess immune reactions and inflammation need not occur, and which are not part of MCTD.

MCTD is caused by immune reactions against self (autoimmunity). The anti-RNP immune response that helps define the disease also appears to mediate some of the damage it induces. The RNP molecules are usually in the nucleus of all human cells, where they help to manufacture messenger RNA, and where the immune system cannot find them. However, in dead or dying cells, RNP molecules can become exposed to the immune system. Since RNP molecules are nearly identical in humans to their counterparts in single celled organisms without immune systems, the human immune system can be fooled into responding to RNP as if it were from a dangerous invader.

The onset of MCTD can occur anytime from early childhood to elderly adulthood, but the average age of onset is 37 years. Approximately 75 percent of patients are female. The point prevalence of MCTD has been found to be 3.8 per 100,000 adults in Norway, and is thought to be similar in many other parts of the world, though much higher prevalence of MCTD has been noted in some countries, notably in Japan.

The symptoms of the following disorders can be similar to those of MCTD. Comparisons may be useful for a differential diagnosis:

Systemic lupus erythematosus (lupus) is a chronic, autoimmune disorder in which multiple targets are attacked, typically including dead cell debris and connective tissue structures. In autoimmune disorders, the body’s own immune system attacks cells and tissues causing inflammation and malfunction of various organ systems. In lupus, organ systems often involved include the skin, kidneys, blood and joints. Many different symptoms can be associated with lupus, but most affected individuals do not experience all of the symptoms. In many patients, lupus may be a mild disorder affecting only a few organ systems. In other patients, it may result in serious complications.


Cryoglobulinemic vasculitis

The symptoms and physical findings of mixed cryoglobulinemia can vary greatly from one individual to another. Many different organ symptoms can be potentially become involved. Some individuals will only exhibit one manifestation of the disorder; others will exhibit symptoms of multiple organ systems.

Mixed cryoglobulinemia is a multifactorial disorder, which means that several different factors such as genetic, environmental and immunogic ones occurring in combination are necessary for the development of the disorder. The specific factors involved in the development of mixed cryoglobulinemia have not been conclusively identified.

Mixed cryoglobulinemia is believed to be a rare disorder, but the exact incidence and prevalence in the general population is unknown. Less than 1% of HCV-infected patients in Northern Europe and North America develop cryoglobulinemia while 2-5% of HCV-infected patients in South Europe develop the disorder. Mixed cryoglobulinemia most often presents in individuals between the ages of 40-60. Females are affected three times as often as males. Approximately 90% of cases of mixed cryoglobulinemia are associated with infection with the hepatitis C virus.

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

A diagnosis of mixed cryoglobulinemia is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a blood test to detect the presence of cryoglobulins.


Moebius syndrome

The abnormalities and severity of Moebius syndrome vary greatly from one person-to-another. The classically accepted diagnostic criteria include: 1) facial paralysis or weakness affecting at least one but usually both sides of the face (7th cranial nerve), 2) paralysis of sideways (lateral) movement of the eyes (6th cranial nerve); and 3) preservation of vertical movements of the eyes. Less often, other cranial nerves, including the 5th, 8th, 9th, 10th, 11th, and 12th may be affected.

Most cases of Moebius syndrome occur randomly for unknown reasons (sporadically) in the absence of a family history of the disorder. The syndrome is listed as Online Mendelian Inheritance in Man (OMIM) Number 15700, with a gene map locus of 13q12.2-q13. Sporadic mutations in PLXND1 and REV3L genes have also been identified in a number of patients and confirmed to cause a constellation of findings consistent with Moebius syndrome when introduced in animal models.

Moebius syndrome affects males and females in equal numbers. The disorder is present at birth (congenital). The exact incidence and prevalence rates of Moebius syndrome are unknown. One estimate places the incidence at 1 case per 50,000 live births in the United States.

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

A diagnosis of Moebius syndrome is based upon the characteristic signs/symptoms, a detailed patient history, and a thorough clinical evaluation. There are no diagnostic tests that confirm a diagnosis of Moebius syndrome. Some specialized tests may be performed to rule out other causes of facial palsy.


钼辅因子缺乏所致亚硫酸盐氧化酶缺乏

Sulfite oxidase deficiency due to molybdenum cofactor deficiency

combined deficiency of sulfite oxidase, xanthine dehydrogenase and aldehyde oxidase

MoCD is caused by disease-causing (pathogenic) variants in the MOCS1 gene (type A), the MOCS2 gene (type B) or the GPHN gene (type C). Variants in the MOCS3 gene have also been reported as a rare cause of MoCD type B. Variants in any one of these genes can disrupt the way the body processes sulfur and sulfur-containing compounds. The resulting accumulation of sulfites in the body is toxic to nerve cells and white matter in the brain and causes nervous system and brain damage that gets worse over time.

MoCD is extremely rare and the exact number of people with this condition is unknown. Less than 200 patients have been reported in the medical literature, and it has been diagnosed in people from all ethnic and racial groups. About half of the patients described have MoCD type A, and most of the rest have MoCD type B. Type C has only been described in a few families. It has been estimated that about 1 in 100,000 to 1 in 200,000 people are born with MoCD.

Isolated sulfite oxidase deficiency (ISOD) has very similar symptoms to MoCD and also has an early-onset and late-onset form. The classic early-onset form begins in infancy with symptoms that include seizures that are difficult to treat and feeding difficulties. Individuals with ISOD develop brain damage that gets worse with time. Involuntary muscle movements, muscle stiffness, breathing difficulties and unusual spine and neck arching can occur. Over time, babies with classic ISOD stop responding to their environment except for an exaggerated startle reflex. They usually do not live for more than a few months. Affected individuals who survive past infancy usually develop displacement of the eye lens (ectopia lentis). In the less common, late-onset form, symptoms occur after an illness, and include muscle spasms, low muscle tone, vison problems and developmental delay. In some individuals, the symptoms go away, and in others, the symptoms get worse. The long-term outlook for people with late-onset ISOD is unknown because it is so rare.  ISOD is caused by variants in the SUOX gene and is inherited in an autosomal recessive pattern in families. Laboratory and genetic testing are necessary to distinguish between MoCD and ISOD.

MOCD is diagnosed based on the symptoms, clinical examination, a detailed family history and laboratory testing. Laboratory tests include blood tests looking for a decreased level of uric acid and urine tests looking for high levels of chemicals called sulfite, S-sulfocysteine, xanthine and hypoxanthine. In addition, an MRI of the brain can be helpful for looking for differences between hypoxic-ischemic brain injury and MoCD.

There is no cure for MoCD. Treatment is based on managing the symptoms. Many different types of specialists may be involved in the care of people with MoCD, including neurologists, developmental specialists, nutritionists, ophthalmologists and gastroenterologists.


Monilethrix

Monilethrix is a rare inherited disorder characterized by sparse, dry, and/or brittle hair that often breaks before reaching more than a few inches in length. The hair may lack luster, and there may be patchy areas of hair loss (alopecia). Another common symptom may be the appearance of elevated spots (papules) surrounding the hair follicles that may be covered with gray or brown crusts or scales (perifollicular hyperkeratosis). When viewed under a microscope, the hair shaft resembles a string of evenly-spaced beads. In most cases, monilethrix is inherited as an autosomal dominant trait.

In most cases of monilethrix, the hair is normal at birth; it may then be slowly replaced by abnormal hair during the first few months to two years of life. In some rare cases, the hair may be abnormal at birth (congenital). The hair may be sparse, dry, lusterless, and/or brittle. In addition, the hair is unusually short and breaks off before growing longer than a few inches.

In most cases, monilethrix is inherited as an autosomal genetic trait. Genetic diseases are determined by two genes, one received from the father and one from the mother.

Monilethrix affects males and females in equal numbers.  The exact number of people affected by this disorder is not known.  Monilethrix may be apparent at birth or by the age of two years.  In some cases, the symptoms may improve at puberty or during pregnancy; in other cases, the symptoms may remain the same throughout life.

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

Alopecia Areata is a rare disorder characterized by the progressive loss of hair.  It often begins suddenly with oval or round bald patches appearing on the scalp; however, other areas of hairy skin may also be involved.  Gradually, the affected skin becomes white and smooth.  The hair may regrow in these areas within weeks; at the same time, additional patches of hair loss may occur elsewhere.  In some cases, hair regrowth may occur in one area of the scalp but not in others; in other cases, the loss of hair may be permanent and lead to baldness.  In a few rare cases, all body hair may be lost.  Cases with onset during childhood tend to be more severe than those with an adult onset.  The exact cause of Alopecia Areata is not known.  (For more information on this disorder, choose Alopecia Areata as your search term in the Rare Disease Database.)

The diagnosis of monilethrix may be confirmed by a thorough clinical evaluation and microscopic examination of the hair. When viewed under a microscope, the hair resembles a string of evenly-spaced beads.


Mosaic trisomy 22

The symptoms and physical findings associated with Mosaic trisomy 22 may depend on the percentage and distribution of cells containing the extra 22nd chromosome. However, the disorder is often characterized by (1) growth and developmental delays, (2) asymmetric body development, and (3) congenital heart diseases.

There are 23 pairs of human chromosomes, or a total of 46 chromosomes. Mosaic trisomy 22 is characterized by an extra copy of the chromosome 22 (trisomy) in some of the body cell populations. This could be due to an error during the division of reproductive cells in one of the parents or during cellular division after fertilization. The disorder can also occur in association with uniparental disomy, an abnormality in which an affected individual inherits both copies of a chromosomal pair from one parent, rather than one copy from each parent. The presence of the additional chromosome 22 in some groups of cells is responsible for the symptoms and physical findings of the disorder.

There have been about 20 reports of live born children with mosaic trisomy 22. It is speculated that children with mosaic trisomy 22 with minimal physical findings and normal development are under diagnosed. The condition appears to occur in females more frequently than in males (approximately 3 females: 2 males).

Symptoms of the following disorders can be similar to those of Chromosome 22, Trisomy Mosaic. Comparisons may be useful for a differential diagnosis.

The diagnosis of trisomy mosaic 22 may be suggested before birth (prenatally) by specialized tests such as ultrasound and amniocentesis. Fetal ultrasound is a non-invasive imaging technique that utilizes high-frequency sound waves to produce image of fetus in the uterus. Abnormal results during ultrasound may prompt to more invasive test such as amniocentesis. During amniocentesis, a sample amniotic fluid (AF) that surrounds the fetus is removed and analyzed. Chromosomal analysis of either AF or chorionic tissues can reveal the presence of mosaic trisomy 22. Karyotyping from AF is not sufficient to confirm a definitive diagnosis. Diagnostic confirmation may require fetal blood sampling or fetal skin biopsy (fetal fibroblast).


Mosaic trisomy 9

Mosaic trisomy 9 is a rare chromosomal disorder in which the entire 9th chromosome appears three times (trisomy) rather than twice in some cells of the body. The term mosaic indicates that some cells contain the extra chromosome 9, while others have the typical chromosomal pair. Mosaic trisomy 9 may be caused by errors during the division of a parent’s egg or sperm or during the division of body tissue cells (somatic cells) early in the development of the fetus.

As noted above, mosaic trisomy 9 is characterized by an extra 9th chromosome (trisomy 9) in some cells of the body (mosaicism). The range and severity of associated features is variable depending on the percentage of cells in the body with an extra chromosome 9 (trisomic cells). In addition, rare cases have also been reported in which all body cells have appeared to be trisomic for all of chromosome 9; such nonmosaic cases are sometimes referred to as full trisomy 9 syndrome. According to investigators, in such patients, characteristic clinical features and affected organs may not substantially differ from those seen with trisomy 9 mosaicism. However, symptoms and findings associated with the latter may tend to be less severe in some cases due to the percentage of cells with an extra chromosome 9. Results of testing for mosaicism can also vary depending on the type of sample (e.g., blood, saliva) and age of the individual.

In individuals with mosaic trisomy 9, the entire 9th chromosome appears three times (trisomy) rather than twice in some cells of the body (mosaicism). Chromosomes are found in the nucleus, or central part, of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as p, a long arm identified by the letter q, and a narrowed region at which the two arms are joined (centromere). Chromosomes are further subdivided into bands that are numbered outward from the centromere. For example, the short arm of chromosome 9 includes bands 9p11 to 9p24, and the long arm includes bands 9q11 to 9q34.

Mosaic trisomy 9 appears to affect males and females of all ethnicities in relatively equal numbers. Some research has found more females with this diagnosis. Since the disorder was originally described in 1973 (Haslam RH), over 100 cases have been reported in the medical literature.

Certain symptoms and findings associated with the following disorders may be similar to those of mosaic trisomy 9. Comparisons may be useful for a differential diagnosis:

Oculo-auriculo-vertebral (OAV) spectrum usually appears to occur sporadically in the absence of a family history. However, in some cases, more than one family member has been affected, suggesting autosomal dominant or autosomal recessive inheritance. Some researchers indicate that the disorder may be caused by the interaction of multiple genes, possibly in association with environmental factors. (For further information, choose OAV spectrum as your search term in the Rare Disease Database.)


Mowat-Wilson syndrome

Mowat-Wilson syndrome (MWS) is a rare genetic disorder that may be apparent at birth or later in childhood. MWS is characterized by intellectual disability, distinctive facial features and seizures. Other congenital anomalies occur in some individuals and can include a gastrointestinal disease known as Hirschsprung disease (40-50% of individuals) in which a narrowing of a portion of the colon is present, eye (ophthalmologic) defects, heart (cardiac) defects, kidney (renal) abnormalities, male genital abnormalities and short stature. Some affected individuals may not be recognized until childhood or adulthood, especially when Hirschsprung disease is not present. MWS is caused by a disease-causing variant in the ZEB2 gene that is usually not inherited from a parent.

MWS is associated with a range of physical symptoms as well as intellectual disability. Most people with MWS have a severe intellectual disability, though a small number have milder features and only moderate intellectual disability. People who have MWS typically have a distinctive facial appearance, absent or severely limited speech and often have seizures. Some physical problems may present at birth or infancy. These include the intestinal disorder Hirschsprung disease in about half, problems with development of the kidneys and male genitalia (hypospadias), congenital heart defects, eye problems and absence of the area of the brain which connects the two cerebral hemispheres (agenesis of the corpus callosum). Later features may include small head size (microcephaly) and short stature. MWS specific growth charts now are available to track growth. Chronic constipation may occur even in those who do not have Hirschsprung disease. Constipation in people with MWS needs investigation in view of the possibility of very short segment Hirschsprung disease.

MWS is an autosomal dominant genetic disorder caused by an variant in the gene called ZEB2. This variant leads to either loss of function (common) or decreased function (rare) of this gene. Genes provide the instructions for making a protein that plays a critical role in the formation of many organs and tissues of the body before birth. When a variant occurs in one copy of this gene, the protein produced may be faulty, inefficient or absent. This affects the development of many organs and tissues throughout the body especially the brain. MWS almost always occurs as a new (sporadic or de novo) variant. This means that in nearly all cases, the gene variant has occurred at the time of formation of the egg or sperm for that child only, and no other family member will be affected. It is usually not inherited from, or carried by, a healthy parent.

MWS affects both males and females. It is estimated to occur in 1 in 50,000-100,000 births. MWS has been described in many different countries and ethnic groups around the world.

Symptoms of the following disorders may overlap with those of Mowat-Wilson syndrome. Comparisons may be useful for a differential diagnosis. There are over 100 syndromes associated with Hirschsprung disease.

MWS is usually diagnosed during infancy or childhood, based upon a thorough clinical evaluation, identification of characteristic physical findings and facial appearance, and information from a variety of specialized tests. Many of these features become more pronounced with time and so the diagnosis is easier to make in older individuals.


Moyamoya disease

Moyamoya disease is a progressive disorder that affects the blood vessels in the brain (cerebrovascular). It is characterized by the narrowing (stenosis) and/or closing (occlusion) of the carotid artery inside the skull, a major artery that delivers blood to the brain. At the same time, tiny blood vessels at the base of the brain open up in an apparent attempt to supply blood to the brain distal to the blockage. These tiny vessels are the moyamoya vessels for which the disease was named. Inadequate blood supply then leads to reduced oxygen delivery to the brain, and it is this oxygen deprivation that causes the signs of moyamoya. One of the symptoms is typically stroke, which results in paralysis of the face, arms or legs, loss of speech, etc., or temporary loss of neurologic function of body parts or speech (transient ischemic attacks, or TIA). Other symptoms that may result include headaches, visual disturbances, developmental delay, and seizures. Approximately 10-30% of cases of moyamoya in Asian countries have a genetic cause. Patients with this arteriopathy that occurs either on a familial or idiopathic basis are said to have moyamoya disease. Patients in whom the artery changes occur in association with another process such as sickle cell disease or Down syndrome are said to have moyamoya disease. In this report, we use the term moyamoya disease as shorthand for both forms.

Although moyamoya disease may occur at any age, there are two peak incidence periods –between the ages of five and ten years in children, and between 30 to 50 years in adults. Children with moyamoya disease may present with a variety of symptoms, but most present with those related to reduced brain blood supply, including stroke, TIAs, headaches, seizures, involuntary movements or occasionally progressive developmental delay.

The causes of moyamoya disease are unknown in many cases. However, it is increasingly recognized that gene changes (mutations or variants) particularly variants that may impair the ability of smooth muscle cells in the walls of affected arteries, to contract normally, are present in many patients. It is also important to note that moymoya is found in association with a number of different underlying disorders, as noted above.

In Japan, moyamoya disease typically occurs in females under the age of 20. In Japan, the disease is estimated to occur in 1 per 300,000 people. Although moyamoya was originally reported in individuals of Japanese ancestry, cases have been reported from elsewhere in Asia as well as from Europe, North and South America and most series reported in the western hemisphere have a minority of patients of Asian descent. Of note, most patients in North America are isolated cases, with recent literature suggesting that less than 4% of cases in this population are familial. (Gaillard 2017)

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

In children, any cause of occlusion or narrowing of blood vessels that supply the brain might present with symptoms similar to moyamoya. These conditions include dissection of neck or brain blood vessels (spontaneous or trauma-induced bleeding into the blood vessel wall, which both narrows the vessel and causes the formation of blood clot in the vessel), sickle cell disease (which causes clotting in major blood vessels in the brain) and inflammatory conditions, such as vasculitis, etc. In adults, strokes have multiple causes, including atherosclerosis of cerebral blood vessels, clots that lodge in brain blood vessels originating in the heart or from narrowed areas in the neck blood vessels, etc. Bleeding within the brain has multiple causes, and a discussion of differential diagnoses is beyond the scope of this article.


Muckle-Wells syndrome

Muckle-Wells syndrome (MWS) is one of the cryopyrin associated periodic syndromes (CAPS) caused by mutations in the CIAS1/NLRP3 gene. These syndromes are characterized by fever, rash and joint pain.

Common symptoms of MWS include recurrent rashes beginning in infancy or early childhood, intermittent fevers, joint pain (usually with no apparent changes in tissue and cartilage), recurrent conjunctivitis (the inflammation of the outer most layer of the eye causing redness, discomfort and discharge from the eye), progressive hearing loss and amyloidosis. Symptoms can be unprecipitated, but can also be triggered by cold exposure as well as stress or exercise. Episodes generally last between 24 to 48 hours.

MWS is usually inherited in an autosomal dominant condition and is caused by a heterozygous mutation in the CIAS1/NLRP3 gene that codes for the protein cryopyrin (NALP3). Mutations in this gene are hypothesized to cause increased activity of a protein complex containing cryopyrin. This protein complex is known as the inflammasome and regulates inflammation in the body. Increased inflammasome activity results in increased release of a protein known as interleukin (IL) 1ß, which leads to symptoms of inflammation such as fever and joint pain.

Since MWS is a newly discovered condition, the actual incidence and prevalence of the disease are difficult to determine.

Symptoms of the following disorders can be similar to those of Muckle-Wells syndrome and there is significant phenotypic overlap. Comparisons may be useful for a differential diagnosis.

Diagnosis of MWS is determined through an evaluation of a patient’s symptoms. Confirmation of the diagnosis is achieved through genetic testing and the identification of a CIAS1/NLRP3 mutation, although not all MWS patients possess a mutation in this gene.


Mucolipidosis IV

Mucolipidosis IV is a rare metabolic disorder characterized by intellectual disability; severe impairment in the acquisition of skills requiring the coordination of muscular and mental activities (psychomotor retardation); diminished muscle tone (hypotonia); clouding (opacity) of the clear portion of the eyes through which light passes (cornea); and progressive degeneration of the nerve-rich membrane lining the eyes (retinal degeneration). Mucolipidosis IV is inherited as an autosomal recessive genetic trait and caused by mutations in the MCOLN1 gene.

The severe form of the disease is called typical mucolipidosis IV, and the mild form is called atypical mucolipidosis IV. Approximately 95 percent of individuals diagnosed with this condition have the severe form.

Mucolipidosis IV is inherited as an autosomal recessive genetic trait. The responsible gene has been isolated and its protein-product, as well as its chromosomal location, determined. The gene, designated MCOLN1, has been tracked to 19p13.3-p13.2 where it encodes for the mucolipin-1 protein. Mutations in this gene result in a deficiency of transport channel receptor protein. The exact function of this protein is still unknown. The effect of mutations on patient and animal model cells indicates a loss of regulation on intracellular traffic which eventually affects various tissue functions.

Mucolipidosis IV is a rare inherited metabolic disorder that affects males and females in equal numbers. The disorder was first identified in 1974 and as of 2010, 70 cases have been reported in the medical literature.  The precise incidence is unknown, but is estimated to be approximately 1:40,000. About 70% of those diagnosed are of Ashkenazi Jewish ancestry.

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

Clinically the more severe cases of MLIV tend to be misdiagnosed as cerebral palsy, a group of developmental diseases with no known genetic cause. This can be easily corrected by testing blood gastrin level, which is increased in MLIV patient due to the inability to produce stomach acid. In milder cases the disease does not affect the development of children, but vision deteriorates with age and some aspects of eye abnormalities exist in the patients.


Mucopolysaccharidosis type 4

Symptoms of MPS IV may include growth delays; a prominent lower face; abnormal sideways and front-to-back or side-to-side curvature of the spine (kyphoscoliosis) or concern for a spine abnormality; an abnormally short neck; knees that are abnormally close together (knock knees or genu valgum); flat feet; abnormal development of the growing ends of the long bones (epiphyses); hip dislocation and arthritis and/or a prominent breast bone (pectus carinatum). Hearing loss, weakness of the legs, and/or additional abnormalities may also occur.

MPS IVA is an autosomal recessive genetic disorder caused by deficiency of the GALNS enzyme due to mutations in the GALNS gene.

MPS IV affects males and females equally often. Estimates of prevalence range from 1/40,000 to 1/200,000 births. MPS IVA (95% of individuals affected by MPS IV) occurs more often than MPS IVB (5% of affected individuals).

Mutations in the GLB1 gene can also be associated with a different lysosomal storage disease called GM1 gangliosidosis, an autosomal recessive genetic disorder that progressively destroys nerve cells in the brain and spinal cord.

MPS IV diagnosis is suggested by the findings of medical history, physical examinations, skeletal X-rays, and urine glycosaminoglycans (GAG) analysis. Excessive amounts of keratan sulfate will usually be present in the urine.


Mucopolysaccharidosis type 1

The specific signs and symptoms seen in MPS I are highly variable and depends on numerous factors including what form of MPS I a child has, when treatment was first started, and how an individual child responds to various treatment options. It is important to note that MPS I is a progressive disorder and therefore the symptoms that a child has are also related to the age of the child at the time of diagnosis. The age of onset, disease severity, degree of intellectual disability, and rate of progression vary significantly among affected individuals.

Mucopolysaccharidosis type I is caused by a variation (mutation, pathogenic sequence variant) in the alpha-L-iduronidase (IDUA) 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, including the brain.

Mucopolysaccharidosis type I affects males and females in equal numbers, with an incidence of about 1 in 100,000 live births for the severe type, and an incidence of about 1in 500,000 live births for the attenuated type. Incidence is the number of people who develop a disorder over a given period of time (e.g. one year). The incidence for MPS disorders collectively is about 1 in 25,000. However, rare disorders, especially milder forms of MPS, often go misdiagnosed or undiagnosed, making it difficult to determine the true frequency in the general population.

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

A diagnosis of mucopolysaccharidosis type I is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. A diagnosis may be suspected in infants with characteristic early signs. Currently newborn screening for MPS I is being implemented in many areas.


Mucopolysaccharidosis type 2

In the neuronopathic form of this disorder, physical and mental development reaches a peak at 2-4 years of age with subsequent deterioration. Recurrent upper respiratory infections, a chronic runny nose, hearing impairment, liver and spleen enlargement, inguinal and abdominal hernias, joint stiffness and multiplex dysplasia, compression of tendons in the wrist (carpal tunnel syndrome), and joint stiffness which can result in reduction of hand function, growth failure and valvular disease commonly occur with this form of MPS II. Coarsening of the facial features with thickening of the nostrils, lips and tongue usually occur between 2 and 4 years of age. Hydrocephalus (fluid buildup in the cavities deep within the brain) is commonly found in this form of MPS II after 4 years of age. Thick skin, short neck, widely spaced teeth, and hearing loss of varying degree are also commonly present. Nodular skin lesions on the arm or the posterior chest wall, extra- high arched feet (pes cavus) and diarrhea may also occur.

The gene responsible for MPS II is known as the iduronate 2-sulfatase (IDS) gene. In many individuals with MPS II, the condition is caused be relatively small changes (e.g., certain missense or nonsense mutations) in the IDS gene, or deletion or insertion of genetic material (e.g., single-base deletions or insertions) that affects gene function. Less commonly, MPS II may result from complete absence or major structural changes of the IDS gene, linking to a neuronopathic disease. Different mutations or structural changes of the gene account for the wide variability of symptoms and findings associated with the disorder (i.e., neuronopathic and non-neuronopathic types).

MPS II typically affects only males, with symptoms becoming apparent at approximately 2-4 years of age. The disorder occurs in approximately 1 in 100,000 to 1 in 170,000 male births. A few affected females have been described, due to the selective inactivation of the X chromosome inherited by the father.

There are many types of mucopolysaccharidoses that have similar symptoms. (For more information, choose mucopolysaccharidosis as your search term in the Rare Disease Database.)

The signs and symptoms of MPS II vary greatly, so the diagnosis cannot be made by physical exam alone. Diagnosis requires documentation of reduced or absent iduronate 2-sulfatase enzyme activity in blood or skin cells. A very simple determination of glycosaminoglycans in the urine may help in screening potential positive patients. Patients with MPSII disease accumulate heparin and dermatan sulfates in the urines. Molecular genetic testing for mutations in the IDS gene is available to confirm the diagnosis. It is always important to rule out a multiple sulfatase deficiency by testing other sulfatase enzymes.

An enzyme replacement therapy, idursulfase (Elaprase), was approved in 2006 by the U.S. Food and Drug Administration (FDA) as a treatment for MPS II. This drug is sponsored by Shire.


Mucopolysaccharidosis type 3

Children with MPS III usually appear healthy at birth, but developmental delay is usually evident by age 2-5 years. A mild speech delay is often one of the first presenting features. Mental and motor development peak by 3-6 years of age, after which intellectual decline usually occurs Severe behavioral disturbances, such as hyperactivity and irritability, are a very common feature of Sanfilippo syndrome, and one of the more difficult aspects of the disorder to manage. The nature of the behavioral symptoms can often lead to an initial diagnosis (misdiagnosis) of autism and/or attention deficit/hyperactivity disorder (ADHD).

All four types of MPS III are caused by variants in different genes that contain the instructions for making enzymes that break down heparan sulfate.

The combined estimated prevalence of Sanfilippo syndrome (types A, B, C and D) is between 1:50,000 and 1:250,000 depending on the population studied. Type A is the most common globally; however, the prevalence of subtypes can vary depending on the region, with type A being more prevalent in Northern Europe and Eastern Europe than in the Mediterranean countries. Type B is the most prevalent subtype in Southern Europe. Types C and D are much less common overall, with estimated global incidences of 1:1,500,000 and 1:1,000,000 respectively.

There are seven types of mucopolysaccharidoses, some of which have similar symptoms. (For more information, choose mucopolysaccharidosis as your search term in the Rare Disease Database.)

To diagnose MPS III, mucopolysaccharides are usually first measured in urine, followed by measurement of enzyme activity in blood or a small skin sample. Increased heparan sulfate in urine, and a decrease in the activity of any one of the four enzymes (shown in the table above) is usually consistent with a diagnosis of MPS III and will identify the MPS III type (A, B, C or D). It is important to know the MPS III type as many of the treatments being developed are only for specific types.


Mucopolysaccharidosis type 7

The most severe cases of MPS VII are characterized by hydrops fetalis, or when excess fluid accumulates in the body before birth. This can result in a stillborn or death shortly after birth. Neonatal jaundice or the yellowing of the skin may occur.

MPS VII is caused by changes (mutations) in the GUSB gene that lead to deficiency of the beta-glucuronidase enzyme. A variety of different mutations in this gene may account for the wide range of symptoms and physical findings as well as the variability in the age of onset.

MPS VII is extremely rare, affecting only about one in 250,000 births. Fewer than 100 cases have been reported in the United States. Males and females are affected in equal numbers.

There are many types of mucopolysaccharidoses that have similar symptoms. (For more information, choose mucopolysaccharidosis as your search term in the Rare Disease Database).

Urinary levels of the mucopolysaccharides (dermatan sulfate, heparan sulfate, and chondroitin sulfate) are increased in affected individuals. The diagnosis of MPS VII may be confirmed by a thorough clinical evaluation that includes a detailed patient history and specialized tests that measure the level of beta-glucuronidase activity in blood or skin cells. Molecular genetic testing for mutations in the GUSB gene is available to confirm the diagnosis. Prenatal diagnosis is possible through amniocentesis or chorionic villus sampling to measure beta-glucuronidase activity or molecular genetic testing for GUSB gene mutations.


Zygomycosis

The most common presentation is a sinus infection (sinusitis) that is accompanied by nasal congestion, nasal discharge and sinus pain. A fever and headache can also occur. If the infection spreads outside the sinuses, symptoms can include tissue loss (necrosis) of the roof of the mouth (palate), disintegration of thin wall of cartilage and bone (septum) that divides the nostrils (septum), swelling of the area around the nose (perinasal area) and redness (erythema) of the skin overlying the sinus and the eye socket (orbit). Sometimes, there is bluish discoloration of the skin near the sinuses or the eye socket due to a lack of oxygen (cyanosis). Sometimes, blurry vision or double vision can develop. If unrecognized and untreated, significant tissue death (necrosis) can occur and the infection can significantly damage facial structures.

Mucormycosis is a fungal infection caused by certain types of molds. These molds are known as mucormycetes. They are found throughout nature (ubiquitous) and can be found in the soil and decaying organic matter like decaying vegetation.

Mucormycosis is a rare fungal infection. The exact number of people who develop this infection in the United States is not known because there is no national surveillance of this infection. One estimate based on a study in the San Francisco area placed the incidence at 1.7 people per every 1,000,000 in the general population. Incidence refers to the number of new diagnoses of a disorder in one year. According to the medical literature, the incidence of mucormycosis is increasing. Mucormycosis has been reported all over the world. This infection can potentially affect individuals of any age, including premature newborns.

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

A diagnosis of mucormycosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A diagnosis of mucormycosis is challenging because the symptoms are common to many conditions including other types of infection. A diagnosis is made by identifying mold in affected tissue and sometimes can be confirmed by a test called a fungal culture. A prompt diagnosis is important so treatment can begin as early as possible.


Mucous membrane pemphigoid

Mucous membrane pemphigoid (MMP) is a group of rare chronic autoimmune disorders characterized by blistering lesions that primarily affect the various mucous membranes of the body. The mucous membranes of the mouth and eyes are most often affected. The mucous membranes of the nose, throat, genitalia, and anus may also be affected. The symptoms of MMP vary among affected individuals depending upon the specific site(s) involved and the progression of the disease. Blistering lesions eventually heal, sometimes with scarring. Progressive scarring may potentially lead to serious complications affecting the eyes and throat. In some cases, blistering lesions also form on the skin, especially in the head and neck area. The exact cause of MMP is unknown.

MMP is characterized by the development of recurring blistering skin lesions affecting the mucous membranes of the body. These lesions may result in scarring of the affected area. Specific symptoms and severity vary from person to person depending upon the specific site(s) involved. It is important to note that affected individuals, in most cases, will not have all of the symptoms listed below.

The exact cause of mucous membrane pemphigoid is unknown. MMP is an autoimmune disorder. Autoimmune disorders are caused when the body’s natural defenses (antibodies or immunoglobulins) against foreign or invading organisms (antigens) begin to attack healthy tissue for unknown reasons. The term autoantibody is used to describe antibodies that are created to attack healthy tissue. The term autoantigen (self antigen) is used to describe the normal tissues and cells of the body that are targeted by the autoantibodies.

Mucous membrane pemphigoid is a rare group of autoimmune blistering disorders that affects females twice as often as males. The average age of onset of MMP is during the seventh decade (60 to 70 years of age). However, the disorder can occur at any age. The exact incidence of MMP is unknown. Because the disorder is difficult to identify, many researchers believe it is under-diagnosed.

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

Bullous pemphigoid (BP) is a chronic skin disease usually affecting the elderly that is characterized by firm, large blisters that develop on normal-appearing or reddened skin usually around cuts or scars. Within weeks, blisters spread to skin of the flexor (muscles that contract or flex) areas, groin, armpit, and the abdomen. Mucous membranes seldom are affected and tend to heal quickly. The blisters have little tendency to spread, but heal quickly when they do. There is, however, severe irritation. Bullous pemphigoid is an autoimmune disorder. (For more information on this disorder, choose bullous pemphigoid as your search term in the Rare Disease Database.)


Mueller-Weiss syndrome

Patients usually present with chronic, atraumatic mid and hindfoot pain without prior trauma that worsens with weight-bearing activity. The pain may be constant or intermittent, but typically worsens over time. Patients also complain of difficulty walking, foot swelling, joint stiffness and limitation of movement, and positional foot deformities including a paradoxical varus hindfoot deformity. In later stages of disease, it is common for MWD patients to have a positive heel raise test on physical exam, indicating posterior tibial tendon dysfunction. Patients may also present with arthritis and anterior knee pain.

The exact cause of MWD is unknown. The most popular theory is that MWD is caused by decreased blood supply to the navicular bone of the foot. Decreased blood supply has many potential underlying causes including nutritional deficiency, smoking, alcohol, corticosteroid use, rheumatologic disorders, hematologic disorders and metabolic disorders. Other theories suggest a multifactorial cause that includes chronic pressure on the navicular bone, suboptimal ossification of the navicular bone during development, congenital causes, dysplasia and primary or secondary osteonecrosis of the navicular bone. Some medical experts think that osteonecrosis of the bone begins due to undiagnosed navicular stress fractures, eventually leading to MWD. MWD does not appear to run in families and there is no evidence of a genetic cause.

The incidence and prevalence of MWD is currently unknown. It typically affects female adults more than male adults at a ratio of approximately 6:1. MWD most typically affects adults ages 40-60 but has been reported in a patient as young as 18 years old. Younger individuals tend to have unilateral deformities, while older individuals tend to have deformities of both feet.

Kohler disease is similar to MWD in that it is also a disorder caused by decreased blood flow to the navicular bone of the foot and causes pain, limping and swelling of the foot. However, it is distinct because it occurs only in childhood, typically in children 3-7 years of age and resolves over time as the child grows. The navicular bone regains its density, size and structure, but symptoms rarely last up to two years. MWD has not been reported in children and will not resolve without intervention. (For more information on Kohler disease search for Kohler in the Rare Disease Database.)

The diagnosis of MWD involves clinical findings, X-ray (radiologic) evidence and pathologic confirmation of the disease. Clinical findings are nonspecific and must be distinguished from those experienced due to trauma, metabolic bone disease, neoplastic bone tumor, secondary osteonecrosis and a previously undiagnosed stress fracture. The appearance of MWD on physical exam may be mistaken for acquired flat feet deformity. Suspicion of MWD can be confirmed with radiographic findings that show wedging and compression of the navicular bone, a comma shaped navicular bone and joint space narrowing.


Muenke Syndrome

The signs and symptoms of Muenke syndrome vary among affected people, and a few people with Muenke syndrome do not have any of the characteristic features of the disorder. For example, some patients may not have craniosynostosis. The symptoms and signs may include:

Muenke syndrome is caused by a specific disease causing (pathogenic) change (variant) in the fibroblast growth factor receptor-3 (FGFR3) gene. Genes are the body’s instruction manual for creating proteins that play critical roles in the body. When a pathogenic variant in a gene occurs, it causes the protein to stop working or to not work properly.  Depending on the function of the protein, it can affect different parts of the body. More than half (>50%) of the people affected with Muenke syndrome inherit a pathogenic variant from a parent. When not inherited from either parent, the genetic change in FGFR3 is new in the patient (de novo).

Muenke syndrome occurs in approximately one in 30,000 livebirths. Muenke syndrome occurs equally in males and females and does not occur more frequently in any specific ethnic group. About one third of individuals with Muenke syndrome are the first to be diagnosed in their families and two-thirds of individuals have a family history of the diagnosis.

There are other genetic syndromes that can cause craniosynostosis, but people with these conditions have different medical problems than a person with Muenke syndrome. These syndromes include Pfeiffer syndrome, Apert syndrome, Crouzon syndrome and Saethre-Chotzen syndrome.

Doctors may suspect of Muenke syndrome in people with:

Management focuses on the treatment of symptoms. This is best achieved in a pediatric craniofacial clinic, which typically includes a craniofacial surgeon and neurosurgeon, clinical geneticist, eye doctor (ophthalmologist), ear, nose and throat doctor (otolaryngologist), pediatrician, radiologist, psychologist, dentist, hearing specialist (audiologist), speech therapist and social worker.


Mulibrey nanism

Mulibrey nanism (MN) is an extremely rare genetic disorder characterized by severe progressive growth delays and abnormalities in multiple organs. Mulibrey is an acronym for MUscles, LIver, BRain, and EYes relating to the original clinical description of the disease. Nanism refers to the short stature (dwarfism) often observed in patients with this disorder. The growth delay usually begins before birth. Non-inflammatory constrictive pericarditis involving fibrotic overgrowth of the sac surrounding the heart is a common feature with a major impact on prognosis. Overgrowth of heart muscle walls (hypertrophy) may add to circulatory problems (congestive heart failure) in these patients as they get older. Short height and facial abnormalities are commonly present. Radiologic findings include slender long bones with thick cortex, narrow medullary channel and fibrous dysplasia, J-shaped sella turcica and a small thoracic cage. The liver is usually enlarged. Additionally, fibrous tissue may build up on the interior of the lungs (pulmonary fibrosis) causing difficulty breathing. Weak muscle tone (hypotonia) is another symptom. The clinical presentation is very variable.

Mulibrey nanism is characterized by progressive growth failure that begins before birth. Infants often have characteristic abnormalities of the head and face including a triangularly shaped face. Yellow discoloration deep within the eyes and other ocular abnormalities may be present but vision is usually normal. Most patients have an enlarged skull (macrocephaly) and a J-shaped sella turcica, which is a depression in the sphenoid bone at the base of the skull. Because this is where the pituitary gland is located, individuals with MN often have underdevelopment of various endocrine glands that leads to hormone deficiencies. The voice of patients with MN is characteristically high pitched.

Mulibrey nanism is caused by harmful changes (pathogenic variants) in the TRIM37 gene located on chromosome 17 (17q22-q23). This gene codes for a protein present in the peroxisome, the part of cell responsible for metabolism. Loss of function of the TRIM37 protein results in a defect in the proper separation of genetic material during cell division. Normal loss of TRIM37 protein activity leads to cell death to prevent mutations in the DNA from multiplying. However, if cell death does not occur, cells with these mutations have a higher likelihood of becoming cancerous. In addition, pathogenetic variants in the TRIM37 gene can impact the number and function of immune cells, leading to an increased risk of severe infections.

Mulibrey nanism is an extremely rare disorder that affects males and females in equal numbers. Approximately 110 patients have been reported worldwide with this condition. Most of the reported cases are from Finland, but this condition has also been diagnosed in North America, South America, Central America, Spain, France and Egypt.

There are other conditions with symptoms similar to mulibrey nanism. Conditions that might be included in a differential diagnosis include Russell-Silver syndrome and Robinow syndrome.

Mulibrey nanism may be diagnosed at birth by a thorough clinical evaluation, characteristic physical findings and specialized tests. The disease can be misdiagnosed as other similar syndromes such as Silver-Russell syndrome, especially in geographic areas where mulibrey nanism is less common.

Constrictive pericarditis may be treated with surgery (pericardiectomy) in symptomatic patients. Constriction-restriction assessments can be useful in determining the underlying cause of congestive heart failure and when to intervene. Diuretics may be prescribed for progressive heart failure. Difficulty breathing due to infection and/or exercise associated with abnormalities of the lungs can be treated with inhaled therapies and asthma medication. Hormone replacement therapy should be offered to children with growth hormone deficiency, delayed puberty, infrequent or very light menstrual periods, hypothyroidism, hypoadrenocorticism and abnormal ovaries or testes. Females with mulibrey nanism should be monitored closely for ovarian tumors, and all patients should be monitored for Wilms’ tumor. Patients who develop cancer can be treated with chemotherapy, surgery and multi-specialty care.


多中心骨质溶解-结节-关节病谱系

Multicentric Osteolysis Nodulosis and Arthropathy Spectrum

Individuals affected by these conditions have skeletal changes that involve thinning or weakening of the bone (multifocal osteoporosis), progressive loss of bone tissue (osteolysis) and low bone mineral density (osteopenia) which lead to degenerative changes in bones of the hands, feet, elbows, shoulders, knees, hips and spine. Loss of bone tissue and density can lead to a short stature and brittle bones that can lead to frequent bone fractures. In some individuals, spine degeneration can cause a sideways curvature of the spine (scoliosis) and forward rounding of the spine (kyphosis).

Multicentric osteolysis nodulosis and arthropathy spectrum disorders are caused by variants in the MMP2 gene or MMP14 gene.

The exact number of people who have these disorders is unknown. Onset is usually between ages six months and six years but can range from birth to 11 years of age.

Winchester syndrome is now considered to be part of this spectrum of diseases called multicentric osteolysis nodulosis and arthropathy spectrum. In the most recent nomenclature of skeletal dysplasias, Winchester syndrome was named MMP14-related multicentric osteolysis, nodulosis, and arthropathy. NORD maintains a separate report on Winchester syndrome because this term is still used in the medical literature. Winchester syndrome has the same characteristics as the other conditions in the multicentric osteolysis nodulosis and arthropathy spectrum and it is characterized by severe osteolysis and generalized osteoporosis; However, in the few people described in the medical literature, no subcutaneous nodules were reported. (For More information on this disorder, choose Winchester Syndrome as your search term in the Rare Disease Database.)

A diagnosis of multicentric osteolysis nodulosis and arthropathy spectrum is based upon identification of characteristic clinical features, a detailed patient and family history and thorough clinical testing that can include molecular genetic testing and an evaluation of enzyme activity.


Multifocal motor neuropathy

Multifocal motor neuropathy is a rare disorder characterized by slowly progressive muscle weakness, primarily of the arms and legs. The disorder is considered to be immune-mediated, which means there is inflammation resulting from abnormal functioning of the immune system and the presence of specific autoantibodies that target a specific protein in the body. Other symptoms including muscles cramps and wasting (atrophy) of muscles can also occur. The term multifocal means arising from two or more spots. The term motor refers to the motor nerves, which are those that carry nerve impulses from the brain to the muscles. The exact, underlying cause of this disorder is not fully understood. The disorder is acquired at some point during a person’s life; a person is not born with the disorder. Multifocal motor neuropathy usually responds to treatment with intravenous immunoglobulin.

Multifocal motor neuropathy is a progressive disorder, this means that the signs and symptoms tend to worsen slowly over time. The main symptom is progressive muscle weakness of the arms and legs. Unlike other neurological disorders affecting the arms and legs, there usually is not any sensory deficits. This means that feelings of tingling or numbness or pain are not associated with the disorder. Muscle weakness often begins in the hands, causing hand weakness and affected individuals may drop objects frequently or have difficulty performing tasks that require fine motor skills such as turning a key in a lock. Fine motor skills are those that require small movements involving the hands and wrists. Some individuals have trouble extending or bending their wrist upward (wrist drop). Reduced grip strength of the hands and reduced dexterity of the hands is seen. Sometimes, muscle weakness starts in the legs. There may be reduced mobility of the toes and foot drop may be early signs. Foot drop occurs when weakness of the muscles involving in lifting the food cause the foot to drop or drag when attempting to walk.

The exact, underlying cause of multifocal motor neuropathy is not fully understood. The disorder is believed to be caused by or related to an abnormal response of the immune system. The immune system is the body’s natural defense system against foreign or invading organisms or substances. The immune system is a complex network of cells, tissues, organs, and proteins that work together to keep the body healthy. Conduction block affecting the motor nerves is a characteristic finding of the disorder. Motor nerves are those that carry nerve impulses from the brain to the muscles. Conduction block is when a nerve impulse does not travel all the way down the nerve and are not carried along properly to the muscles. Multiple motor nerves are damaged by this disorder, although the exact reason is not fully understood. Researchers believe that conduction block in multifocal motor neuropathy is reversible.

Multifocal motor neuropathy affects both men and women, although men are more frequently affected than women by a ratio of about 2.7:1. Men also tend to be diagnosed at a younger age. The median age of onset is 40 years old, although the disorder has been reported individuals ranging from 20-80 years of age. In a handful of instances, the disorder has occurred in children (pediatric cases). Multifocal motor neuropathy is estimated to affect about 0.6 per 100,000 in the general population. Because rare disorders often go undiagnosed or misdiagnosed, determining their true frequency in the general population is difficult.

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

A diagnosis of multifocal motor neuropathy is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Asymmetrical muscle weakness without sensory problems (e.g. numbness, tingling, etc.) are the main signs of multifocal motor neuropathy. Diagnostic criteria for this disorder have been proposed by several groups. One set of guidelines (Van Schaik IN, 2010) is published by the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS).

The treatment of multifocal motor neuropathy may require the coordinated efforts of a team of specialists. General internists, specialists in diagnosing and treating disorders of the central nervous system and brain (neurologists), specialists in diagnosing and treating disorders of the immune system (immunologists), specialists in diagnosing and treating disorders of the skeleton and muscles (orthopedists), and other healthcare professionals may need to systematically and comprehensively plan treatment. Physical therapy to strengthen muscles may be of benefit to some individuals.


Multiple endocrine neoplasia type 1

Multiple endocrine neoplasia (MEN) type 1 is a rare genetic disorder characterized by multiple tumors arising from cells of specific neuroendocrine tissues. The endocrine system is the network of glands that secrete hormones into the bloodstream to reach their target organs along the entire body. These hormones regulate the chemical processes (metabolism) that influence the function of various organs and activities within the body. Hormones are involved in numerous vital and metabolic processes, including regulating heart rate, body temperature and blood pressure, as well as cell differentiation and growth.

MEN type 1-associated symptoms depend on which glands are affected by the overgrowth of tissue (hyperplasia) or tumor formation. Although most tumors are benign (noncancerous), tissue overgrowth or tumor formation causes the affected glands to become hyperactive and produce excess hormones. Elevated hormone levels are the main cause of MEN type 1-associated signs and symptoms. Certain tumors, such as gastrinomas and carcinoid tumors can potentially become malignant, and they still represent the two main causes of MEN type 1-associated death. The clinical expression of MEN type 1 is highly variable even within members of the same family and identical twins.

MEN type 1 is a rare genetic disorder caused by loss-of-function variants of the MEN1 gene. The MEN1 gene encodes a nuclear protein known as menin. The exact role of menin is not fully understood. The MEN1 gene is a tumor suppressor gene, a gene that when it operates normally may have several functions including inhibiting cell division, repairing and replicating DNA and instructing cells when to die (a normal process called apoptosis). When tumor suppressor genes malfunction, certain cells may continue to grow and reproduce causing tumor formation.

MEN type 1 affects males and females in equal numbers. It affects approximately 1 in 30,000 individuals. Some researchers think that many cases of MEN type 1 go undiagnosed, making it difficult to determine its true frequency in the general population. The onset of the disorder can vary widely, and it has been identified in children as young as 5 and adults as old as 80. MEN type 1 was first recognized as a genetic disorder in 1954.

Symptoms of the following disorders can be similar to those of MEN type 1. Comparisons may be useful for a differential diagnosis.

Affected individuals may receive a diagnosis of MEN type 1 following a thorough clinical evaluation, a detailed patient and family history and the identification of at least two of the three characteristic endocrine tumors associated with the disorder (i.e., parathyroid and pituitary tumors and islet cell tumors in the pancreas or duodenum). Individuals with only one of the associated tumors and a positive family history of the disorder may also receive a diagnosis of MEN type 1. A variety of tests to detect elevated levels of certain hormones in the blood may be necessary to aid in the early identification of tumors. For example, identification of elevated levels of PTH together with hypercalcemia can indicate the presence of a parathyroid tumor. A variety of imaging scans may be performed to aid in identifying the size and location of specific tumors.


Multiple endocrine neoplasia type 2

Multiple endocrine neoplasia type 2 (MEN2) is a rare genetic polyglandular cancer syndrome, characterized by the presence of medullary thyroid carcinoma (MTC) and an increased risk of develop other specific tumors affecting other glands of the endocrine system.

The onset, progression and specific symptoms of each case of MEN2 can vary. Some individuals may only develop mild symptoms; others may develop serious, life-threatening complications. Some individuals may develop symptoms during infancy or early childhood; others may not develop symptoms until adolescence or young adulthood. Some cases of MEN2 may not become apparent until later during adulthood. Clinical features (phenotype) are associated with a specific RET gene variant, and, therefore, MEN2A and MEN2B are associated with different RET gene variants.

MEN2 is caused by a disease-causing (pathogenic) variant in the RET gene. The RET gene is a proto-oncogene, a gene that, when altered, plays a role in the development of cancer. The RET gene encodes a protein, the RET tyrosine kinase membrane receptor.

MEN2 affects males and females in equal numbers. It has been estimated to affect 1 in 40,000 people in the general population for all the MEN2A subtypes, and from 1/350,000 to 1/700,000 for the extremely rare MEN2B variant. Some researchers think that many cases of MEN2 go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of these conditions in the general population.

Symptoms of the following disorders can be similar to those of MEN2. Comparisons may be useful for a differential diagnosis.

Affected individuals may receive a clinical diagnosis of MEN2 following a specific clinical evaluation for MEN2-associated tumors, a detailed patient and familial history and the identification of characteristic features.

The treatment of MEN2 may require the coordinated efforts of a team of specialists. Endocrinologists, surgeons, cancer specialists (oncologists) and other healthcare professionals may need to plan the treatment systematically and comprehensively. Treatment is directed toward the specific symptoms that are apparent in each individual and may include surgical removal of tumors and drugs to counteract the effects of excess hormones or replacement of hormones no longer produced by the body (i.e., following surgical removal of a gland).


Multiple myeloma

Multiple myeloma is a rare form of cancer characterized by excessive production (proliferation) and improper function of certain cells (plasma cells) found in the bone marrow. Plasma cells, which are a type of white blood cell, are produced in the bone marrow and normally reside there. Excessive plasma cells may eventually mass together to form a tumor or tumors in various sites of the body, especially the bone marrow. If only a single tumor is present, the term solitary plasmacytoma is used. When multiple tumors are present or the bone marrow has greater than 10% plasma cells, the term multiple myeloma is used.

The specific symptoms, age of onset, and rate of progression of multiple myeloma varies from patient to patient. Some affected individuals will not exhibit any symptoms (asymptomatic or smoldering). Multiple myeloma may progress to cause life-threatening complications. It is important to note that affected individuals will not have all the symptoms listed below.

The exact cause of multiple myeloma is not known. Symptoms occur as a result of a process that is initiated by the abnormal multiplication of plasma cells in bone marrow. Scientists suspect there may be a variety of causes that may include environmental factors (e.g., the effects of exposure to radiation), genetic abnormalities, and/or additional factors that may play varying contributing roles. Exposure to dioxin has been associated with an increased risk of myeloma.

Multiple myeloma is a rare cancer that is slightly more common in males than females. In 2019, over 32,000 individuals in the United States were diagnosed with this disease. It is believed that approximately 100,000 Americans currently have the disease.

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

Waldenstrom macroglobulinemia is a lymph and blood cell disorder. Abnormally large quantities of homogeneous protein molecules are present in the blood. The disorder may run in families and occurs after the sixth decade. An enlarged spleen and liver with abnormalities of the lymph glands are the most frequent symptoms. Weakness, anemia, fatigue and excessive bleeding, especially from the nose and mouth, also occur. (For more information on this disorder, choose Waldenstrom as your search term in the Rare Disease Database.)


Multiple Sclerosis

Multiple sclerosis (MS) is a chronic neuroimmunologic (both the nervous system and the immunological system are involved) disorder of the central nervous system involving the brain, spinal cord and optic nerves. By means of a mechanism not clearly understood, the protective fatty, insulating substance called myelin sheath that covers the nerve is destroyed. The inflammatory attacks that produce the characteristic scarring (plaques or patches) of the myelin sheath occurs unpredictability, vary in intensity, and at many sites thus the name, multiple sclerosis. During the course of the disease, patients may have attacks (relapses or exacerbations), gradually worsen (progression), or stabilize. The randomness of the location of damage can result in a wide range of neurological symptoms, which may vary from person to person. Recently it has been learned that the nerve fibers themselves (axons), in addition to the myelin sheaths, are also affected early in the MS disease process. Damage to axons is irreversible thus clinicians recommend early treatment with one of the disease-modifying agents (see below).

The symptoms of multiple sclerosis may vary greatly. Some people may have visual impairment (including central visual fields), double vision (diplopia), or involuntary rhythmic movements of the eyes (nystagmus). People with multiple sclerosis may also experience impairment of speech, numbness or tingling sensation in the limbs and difficulty walking. Dysfunction of the bladder and bowel may also be present along with sexual dysfunction. Multiple sclerosis is rarely fatal; the average life expectancy is 93 percent of that of the general population. In some cases however, changes in mobility make it necessary to use a cane, crutches, or other mobility devises. In a limited number of patients, the disease may result in life-threatening complications.

The exact cause of multiple sclerosis is not known. Nevertheless, most clinical investigators agree that MS may be the result of an abnormal immunopathologically likely autoimmune in a genetically susceptible person in response to one or more environmental factors.

The number of people with MS has been estimated to be between 300,000 and 500,000 in the US and 2.5 million people worldwide. However, this may be an underestimate because these figures are based on data collected in the 1970’s, prior to the use of MRI for diagnosis. Twice as many females as males are affected. The disorder may appear at any age, although the diagnosis is most often made between 20 and 50 years of age.

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

Amyotrophic lateral sclerosis (ALS) is a disease of the motor neurons that send signals to the skeletal muscles. It generally affects both the upper and the lower muscle groups and results in the progressive weakness and wasting away of the muscles involved. There are several varieties of ALS. The early symptoms may include slight muscular weakness, clumsy hand movements and difficulty performing fine motor tasks. Weakness in the legs may result in clumsiness and tripping, and slurring of speech, difficulty swallowing and shortness of breath may also be present. Other symptoms may include muscle stiffness and coughing. Sensory and autonomic problems are not part of ALS among several distinguishing features differing from MS (For more information on this disorder, choose amyotrophic lateral sclerosis as your search term in the Rare Disease Database.)


Multiple sulfatase deficiency

Multiple sulfatase deficiency (MSD) is an ultra-rare genetic disorder in which all of the known sulfatase enzymes are unable to be fully activated by formylglycine-generating enzyme (FGE), which is encoded by the SUMF1 gene. Because of the multisystemic importance of sulfatases, this disorder affects many parts of the body. While neurologic impairment is universal, major systemic symptoms can be variable and include bone abnormalities, coarsened facial features, deafness, and an enlarged liver and spleen (hepatosplenomegaly). Because of deficient activation of steroid sulfatase, the skin of children affected by MSD can be usually dry and scaly (ichthyosis).

Classically, the subtypes of MSD are defined by the age at symptom onset: neonatal, severe late infantile, mild infantile, and juvenile. The clinical relevance of these divisions is unknown, as subtle symptoms are present in infancy across all types. Because MSD is the result of a variable degree of deficiency across all human sulfatases, the systemic symptoms can be variable.

Multiple sulfatase deficiency is an autosomal recessive disorder caused by a change (mutation) in the SUMF1 gene. This gene allows cells to make an enzyme called FGE (formylglycine-generating enzyme) that activates all sulfatases within the cell. Without activation, sulfatases are not able to do their jobs in the cell. The missing sulfatases are directly responsible for the changes in the body seen in MSD. More severe forms of the disease are associated with SUMF1 mutations that lead to the production of an unstable form of FGE, while the more mild forms are due to mutations that lead to reduced but correctly functioning FGE.

Multiple sulfatase deficiency is an ultra-rare disorder with a wide spectrum of disease.   To date, over one hundred patients have been reported in the literature with 50 of those patients confirmed alive by patient organization registries. This number may be underestimated due under diagnosis or lack of reporting.  Males and females are equally affected and no ethnic predisposition has been identified.

Symptoms of the following disorders can resemble those of multiple sulfatase deficiency. In particular, disorders caused by single sulfatase deficiencies, such as arylsulfatase A in metachromatic leukodystrophy, share many similarities. Comparisons are useful for differential diagnosis:

Metachromatic leukodystrophy (MLD) is a rare hereditary disease characterized by accumulation of fats called sulfatides. This causes the destruction of the protective fatty layer (myelin sheath) surrounding the nerves in both the central nervous system and the peripheral nervous system. Three types of MLD ultimately affect both intellectual and motor function. Symptoms vary by type but can include difficulty talking, seizures, difficulty walking, personality changes, and behavior and personality changes. MLD is caused by mutations in the ASA gene.  All forms of MLD are progressive. (For more information on this condition, choose metachromatic leukodystrophy as your search term in the Rare Disease Database.)

There are currently no targeted therapies for MSD, and treatment is supportive and based upon symptoms. Care for patients with MSD requires a multidisciplinary team to evaluate the many body systems that may be affected by this disease. Due to the very broad spectrum of clinical problems a comprehensive approach is recommended. Depending on the needs of the child, important members of the team may include neurology and/or metabolism, complex care pediatrics, gastroenterology, nutrition, urology, orthopedics, and physiatry.


Multiple system atrophy

The range, severity, and distribution of symptoms vary greatly among affected individuals. For example, some may initially have only mild symptoms for several years; others may experience severe symptoms early in the course of the disease. Symptoms of MSA may vary depending upon which form of MSA predominates. The disorder can cause the progressive loss of motor skills and approximately 50% of individuals are wheelchair-bound within 5-6 years of the onset of motor symptoms. Eventually, affected individuals may become confined to bed and experience life-threatening complications.

The exact underlying cause of MSA is unknown. It appears to occur randomly for unknown reasons (sporadically). Researchers have suggested that multiple environmental or genetic factors are important, but more research is needed.

MSA appears to affect males and females in equal numbers. The peak onset of MSA is between 55-60 years of age, with a range from 30 to over 90 years. The incidence of MSA in the United States is estimated at 0.6 cases per 100,000 people per year in the general population giving a current estimate of about 1,900 new cases per year in the USA. A prevalence study in London, UK, gave an age-adjusted figure of 4.4 living cases per 100,000 population at any one time, which would currently translate to about 14,000 living cases in the USA. There is about 1 living case of MSA in the population for every 40 cases of Parkinson’s disease, but because survival in MSA is shorter than for PD, about 1 new MSA case presents every year for about every 20 who present with PD.

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

Parkinson’s disease (PD) is a slowly progressive neurologic movement disorder characterized by involuntary, resting tremor, muscular stiffness or lack of flexibility (rigidity), slowness of movement (bradykinesia) and difficulty controlling voluntary movements. It also commonly causes autonomic symptoms and, in advanced, older, patients, dementia. Degenerative changes occur in areas deep within the brain (substantia nigra and other pigmented regions of the brain), resulting in decreasing levels of the neurotransmitter dopamine in the brain. Dopamine is a highly specialized brain chemical that sends a signal to other nerve cells, and participates in the regulation of body movements. Parkinson’s disease usually begins in late adulthood. It is slowly progressive; however, it may not become incapacitating for many years. (For more information on this disorder, choose Parkinson’s disease as your search term in the Rare Disease Database.)


早衰-身材矮小-色素痣综合征

Progeria-short stature-pigmented nevi syndrome

progeriod short stature with pigmented nevi

Mulvihill-Smith syndrome is diagnosed based on a series of symptoms described in the scientific literature. There can be some variation of symptoms between affected individuals. The core symptoms include the following:

The cause of Mulvihill-Smith syndrome is not presently known. All reported affected individuals have been isolated and independent cases. This makes it likely that the disease results from a new spontaneous mutation in a gene or gene(s) or caused by other genetic defects (chromosome abnormalities). The possibility that the disease may be inherited (autosomal recessive inheritance) has been suggested in one scientific paper. Autosomal recessive diseases occur when the affected individual inherits two abnormal copies of the gene, one from each parent. It is also possible that the disease is both autosomal recessive and spontaneous, with one mutation inherited from one parent and the other mutation arising spontaneously. No specific genes associated with Mulvihill-Smith syndrome have been identified, so this condition cannot be identified through genetic testing. Mulvihill-Smith syndrome is diagnosed by the symptoms that have been described above.

Mulvihill-Smith syndrome is an extremely rare disorder (11 reported cases) that, in theory, affects males and females in equal numbers. Most of the reported affected individuals, however, have been males (7 males, 4 females).

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

The diagnosis of Mulvihill-Smith syndrome may be suspected upon the identification of characteristic described in the Signs and Symptoms section above. A diagnosis may be confirmed based upon a thorough clinical evaluation, a detailed patient history and a variety of specialized tests. For example, hearing tests may be performed to determine the range and severity of hearing impairment, blood tests may be performed to analyze levels of immune cells and a detailed physical exam would look at many physical traits such as skin conditions. The clinical diagnosis by a physician is based on whether the individual meets enough of the core criteria of Mulvihill-Smith syndrome and following the exclusion of all other diseases or disorders that share some similar symptoms.


Muscular Dystrophy, Becker

Becker muscular dystrophy is in the category of inherited muscle wasting diseases caused by a gene abnormality (mutation) that results in deficient or abnormal production of the dystrophin protein (dystrophinopathies). The abnormal gene is called DMD and is located on the X chromosome. Becker muscular dystrophy follows x-linked recessive inheritance so it mostly affects males, but some females are affected. Becker muscular dystrophy usually begins in the teens or early twenties and symptoms vary greatly between affected individuals. Muscle deterioration progresses slowly but usually results in the need for a wheel chair. Muscles of the heart deteriorate (cardiomyopathy) in some affected individuals, and this process can become life-threatening. Learning disabilities involving visual abilities may be present.

Symptoms of Becker muscular dystrophy usually begin in the teens or late twenties. Initial symptoms may include cramping during exercise and reduced stamina during exercise. Muscle gradually deteriorates in the hips, pelvis, thighs and shoulders that can lead to walking on toes with the stomach forward. Shortening of muscle fibers can result in the inability to move certain muscles (contractures). The progression of BMD is slower and more variable than Duchenne muscular dystrophy but usually results in the need for a wheel chair. The heart muscle is also affected and can result in feeling breathless, fluid accumulation in the lungs and swelling in the feet and lower legs. Dilated cardiomyopathy is the most common cause of death in individuals with BMD, and most affected individuals die in their mid 40’s.

Becker muscular dystrophy is caused by abnormalities (mutations) in the DMD gene that is responsible for the production of the dystrophin protein. Dystrophin is necessary for the stability and protection of muscle. The gene mutation causes the dystrophin protein to be shorter than normal and not function normally.

Becker muscular dystrophy occurs in approximately 1 in 30,000 male births.

Symptoms of the following disorders can be similar to those of Becker muscular dystrophy (BMD). Comparisons may be useful for a differential diagnosis:

Duchenne muscular dystrophy is an x-linked recessive genetic disease that is also caused by mutations in the DMD gene. The DMD gene mutations that cause Duchenne muscular dystrophy result in little or no dystrophin protein to be made. Symptoms usually begin in early childhood and progress rapidly. The disease is initially characterized by delays in sitting and standing and difficulty climbing. Children often need a wheel chair by the age of twelve. A disease affecting the heart muscle (cardiomyopathy) occurs in the teenage years and can be life threatening. (For more information about this condition, choose Duchenne as your search term in the Rare Disease Database.)