Lichen Sclerosus

Lichen sclerosus is a chronic inflammatory skin disorder that most commonly affects women before puberty or after menopause. Although rare, it can also be seen in men. When found in males, the disease is known as balanitis xerotica obliterans.

Lichen sclerosus usually affects the external genitalia (vulva or penis) and/or the area around the anus (perianal region). Sometimes, it is accompanied by intense (intractable) itching, burning, and pain. If the disease is severe, even minor abrasions or chaffing can cause bleeding, tearing, and blistering. The scarring that results from untreated lichen sclerosus produces problems with urination, defecation, and intercourse. The presence of thin, easily irritated, and torn skin affects physical activity and clothing choice.

The exact cause of lichen sclerosus is not known. Most research indicates it is an autoimmune condition. Autoimmune disorders arise when the body’s natural defenses against foreign or invading organisms (e.g., antibodies) begin to attack healthy tissue for unknown reasons. Some cases of lichen sclerosus may be linked to formation of certain antibodies (e.g. a thyroid protein (thyroglobulin), or certain cells that line the walls of organs).

Lichen sclerosus affects mostly females, usually between the ages of 40 and 60 years. Females are six times as likely to be affected as are males. Younger females and males have also been identified in the medical literature in the United States. Female children under the age of thirteen have also been reported with the condition.

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

Morphea or localized scleroderma occurs in adults and children. Recent studies indicate that up to 20% of those with morphea, particularly post-menopausal women, may have changes that resemble lichen sclerosus in the genital area. Moreover, lesions of morphea may co-exist with lichen sclerosus on the body. For this reason, those with lichen sclerosus should have their skin examined for signs of morphea and those with morphea should be checked for lichen sclerosus.


Liddle syndrome

There is no overt set of symptoms that is distinct in persons with Liddle syndrome to uniquely distinguish it from other disorders. The lack of an easily observable set of traits in the patient’s physical examination, other than an elevated blood pressure reading, presents difficulties for diagnosis (see sections below on Diagnosis and Related Disorders).

Liddle syndrome is an autosomal dominant genetic disorder caused by mutations in the genes that code for the epithelial sodium channel (SCNN1A, SCNN1B, and SCNN1G). These mutations result in an increase in ENaC activity, sodium and water retention and hypertension.

Estimates of how common Liddle syndrome is vary. A survey of symptoms of veteran patients with hypertension found that 6% met the non-genetic diagnostic criteria for Liddle syndrome (Tapolyai et al. 2010), which is a much higher prevalence than confirmed cases by genetic testing. Gene sequencing studies of early onset hypertension have suggested a population prevalence of about 0.9–1.5% among those who develop hypertension before age 30 (Liu et al. 2018). While most confirmed cases of Liddle syndrome are identified in children through evaluation of early-onset hypertension, cases have also been identified later in life (Pepersack et al. 2015).

Several disorders can produce symptoms similar to Liddle syndrome. These include a mutation to the mineralocorticoid receptor which makes it sensitive to progesterone, mineralocorticoid excess caused by mutations to 11-beta-hydroxysteroiddehydrogenase-type-II enzyme, glucocorticoid remediable aldosteronism and familial glucocorticoid resistance. Excess natural licorice consumption can also cause a transient Liddle-like syndrome. Some similar conditions can also have an autosomal dominant inheritance pattern. For example, primary aldosteronism (Conn’s syndrome) can produce similar symptoms and labs to Liddle syndrome with the exception of a high serum aldosterone level.

Diagnosis of Liddle syndrome often includes identification of symptoms, patient and family history and laboratory testing (e.g., plasma renin activity, serum aldosterone levels). Diagnosis begins with identification of resistant hypertension, and then analysis of laboratory values. This is followed by genetic testing. Clinicians consider the diagnosis of Liddle syndrome when evaluating secondary causes of hypertension and/or difficult-to-control hypertension. Resistant hypertension is defined by the American Heart Association as blood pressure that remains above goal despite optimal doses of 3 antihypertensive agents of different classes, one ideally being a diuretic.

The goal of treatment is to resolve the patient’s hypertension, lowering blood pressure measurements to achieve guideline targets of control. A controlled blood pressure reduces cardiovascular risk and often has a positive effect on the patient’s overall health, including mental health.


Limb-girdle muscular dystrophy

Limb-girdle muscular dystrophies (LGMD) are a group of rare progressive genetic disorders that are characterized by wasting (atrophy) and weakness of the voluntary muscles of the hip and shoulder areas (limb-girdle area). Muscle weakness and atrophy are progressive and may spread to affect other muscles of the body. Many different subtypes have been identified based upon abnormal changes (mutations) of certain genes. The age at onset, severity, and progression of symptoms of these subtypes may vary greatly from case to case, even among individuals in the same family. Some individuals may have a mild, slowly progressive form of the disorders; other may have a rapidly progressive form of the disorder that causes severe disability.

Although there are some common themes recognizable in the main types of LGMD, the age at onset, severity, and progression of symptoms associated with LGMD may vary greatly from case to case, even among members of the same family. Some cases of LGMD may have onset during adulthood, mild symptoms, and slow progression; others may have onset during childhood and early severe disability such as difficulty climbing stairs and walking. Some individuals eventually require a wheelchair. In most cases, childhood onset of LGMD results in a more severe disorder that progresses more rapidly than adolescent or adult onset cases.

LGMD is a genetic disorder that is inherited as either an autosomal recessive or dominant trait. The autosomal recessive forms are estimated to account for 90 percent of cases. Genetic disorders are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

LGMD affects males and females in equal numbers. The incidence of the disorder is unknown. The prevalence of LGMD is unknown, but estimates range from one in 14,500 to one in 123,000. The age of onset can vary greatly even among individuals of the same family. The relative frequencies of the different types of LGMD vary from population to population, but worldwide LGMD2G, 2H and 2J are extremely rare.

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

Within the LGMD group, it is important to reach a precise diagnosis so that the patient and his or her family may be given correct genetic advice, as well as appropriate guidance for the management of complications, which can vary from disease entity to disease entity. This particularly relates to the risk of cardiac or respiratory complications. The precise testing available today may make it possible for individuals who were given a presumed diagnosis of LGMD in the past to be reappraised and given a more precise molecular diagnosis.


Liposarcoma

As previously mentioned, most patients who are diagnosed with liposarcoma do not have any early symptoms and it can go unnoticed during the initial stages of the disease until the tumor has grown to a large enough size to compress neighboring tissues and cause pain or decreased function. It can sometimes be noticed as a deep-seated mass to touch. Liposarcoma, as with all other cancers, can present with non-specific symptoms such as fevers, chills, fatigue, night sweats and weight loss. If the tumor is retroperitoneal in location, it can present with specific symptoms in the abdomen, including abdominal or flank pain, swelling, and constipation or the sensation of feeling full sooner than expected after eating.

The specific cause of liposarcoma is still unknown. Clinically, it can be first noticed particularly in the extremity in an area of recent trauma where the patient may find a mass, however the cause and effect are quite likely purely coincidental. Liposarcoma generally is attributed to a change in some of the genes that are normally present in fat cells. A series of abnormalities in these genes (mutations or DNA alterations) can lead to malignant changes characterized by uncontrollable growth.

Liposarcoma is a soft tissue sarcoma, affecting approximately 2000 individuals each year in the United States. It affects men more than women, and more specifically middle-aged men ranging from 50 – 65 years of age. Children are rarely diagnosed, but when liposarcoma does occur in children, it is usually during adolescence. There is no specific ethnicity in which liposarcoma is more common. Certain risk factors have been shown to predispose individuals to developing soft tissue sarcomas, such as liposarcoma, including prior radiation, familial cancer syndromes, damage to the lymph system, and long-term exposure to certain toxic chemicals such as vinyl chloride, a chemical used to make plastic.

There are other diseases that can present very similarly to liposarcoma. Lipoma is a non-cancerous (benign) tumor that can look like liposarcoma, but it is usually softer and feels like a mass directly below the skin rather than in deeper parts of the body. A lipoma cannot transform into a liposarcoma. Other soft tissue tumors, such as undifferentiated pleomorphic sarcoma, lipomatous hemangiopericytoma, non-lipogenic sarcoma and gastrointestinal stromal tumors, can also look like liposarcoma when initially evaluated under a microscope.

The most critical step in the diagnosis of liposarcoma involves taking a biopsy of the mass of concern. A biopsy is when tissue is retrieved from the tumor in order to be evaluated under the microscope to assess whether or not the tissue has tumor-specific features. Since many of these tumors are deeply embedded into the body, imaging such as ultrasound can be used to guide where the needle is relative to the mass and ensure that the tissue sample is retrieved specifically from that mass.


Lissencephaly

Newborns with lissencephaly type 1 who have no underlying syndrome are said to have isolated lissencephaly sequence (ILS). In addition to lissencephaly, those with the condition may have other associated brain malformations, such as absence or underdevelopment of the corpus callosum, which is the thick band of nerve fibers that join and carry messages between the brain’s two cerebral hemispheres. Affected infants often also have microcephaly, seizures, and severe or profound intellectual disability. In addition, those with the condition may have a normal facial appearance or subtle facial changes, such as a relatively small jaw (micrognathia) or a slight indentation of the temples (bitemporal hollowing).  Additional symptoms and findings may include feeding difficulties, growth failure, abnormally diminished muscle tone (hypotonia) early in life, and increased muscle tone (hypertonia) later during infancy, and impaired motor abilities.

Lissencephaly may be due to various non-genetic and genetic factors. Such factors may include intrauterine infection, insufficient supply of oxygenated blood to the brain (ischemia) during fetal development, and/or different gene mutations.

The overall incidence of lissencephaly is rare and estimated around 1.2/100,000 births.

There is a related brain abnormality, lissencephaly type II, which is also known as cobblestone lissencephaly. It is characterized by severe brain malformations and associated obstructive hydrocephalus. Obstructive hydrocephalus is a condition in which there is obstructed flow of the fluid surrounding the brain and spinal cord (cerebrospinal fluid), resulting in increasing fluid pressure in the brain. Associated symptoms and findings may include abnormal enlargement of the ventricles of the brain, rapid enlargement of the head, and seizures. Lissencephaly type ll is a major manifestation of Walker-Warburg syndrome (see below).

When the suspicion is high for lissencephaly type 1 because of family history and/or prenatal ultrasound screening, it is possible that the condition may be confirmed by specialized testing during pregnancy, such as cell-free fetal DNA, amniocentesis or chorionic villus sampling (CVS).


Listeriosis

Listeriosis is a rare but serious infectious disease caused by the bacterium Listeria monocytogenes, which is predominantly transmitted to humans through the consumption of contaminated food. Clinical syndromes associated with listeriosis include febrile gastroenteritis, invasive disease (bacteremia, meningitis, meningoencephalitis) and pregnancy-associated infections causing spontaneous abortions, stillbirth, premature labor and neonatal disease. Approximately 20% of listeriosis cases are fatal. Listeriosis most often affects pregnant women and their newborns, adults aged 65 and older and individuals with weakened immune systems. Prompt recognition and treatment of the disease is necessary to avoid several serious complications.

Symptoms associated with listeriosis may vary widely, ranging from mild febrile gastroenteritis to invasive disease (which occurs when the bacteria spread beyond the gastrointestinal tract) causing severe illness. People who are not pregnant most often present with bacteremia (bacteria in the blood), meningitis (infection of the meninges, the membrane surrounding the brain and spinal cord) or meningoencephalitis (infection of the meninges and brain). Common presenting symptoms in patients with bacteremia, meningitis, or meningoencephalitis include fever, muscle aches, headache, stiff neck, malaise, ataxia (loss of balance), convulsions and mental status changes, such as confusion. Less common clinical syndromes include endocarditis (infection of the lining of the heart), pneumonia, osteomyelitis (infection of the bone), septic arthritis (infection of the joint), abscesses of the brain or liver, peritonitis (infection of the membranes lining the abdominal cavity) and endophthalmitis (infection of structures within the eye). Symptoms secondary to these conditions depend on the anatomical site of infection and may include abdominal pain, bone pain, respiratory distress, pneumonia and heart failure. Outbreak investigations have demonstrated that listeriosis can cause febrile gastroenteritis, a noninvasive syndrome, in healthy individuals. Patients with febrile gastroenteritis typically experience diarrhea, fever/chills, fatigue, headache, abdominal pain and nausea.

Listeriosis is caused by the bacterium Listeria monocytogenes. Nearly all cases of listeriosis (other than neonatal listeriosis) occur from eating contaminated food products, especially ready-to-eat, refrigerated foods. Unlike most foodborne bacterial pathogens, L. monocytogenes can grow at refrigeration temperatures. Listeria organisms are commonly found in the environment, including water, soil, mud and decaying vegetation. L. monocytogenes can be introduced into slaughterhouses and food manufacturing plants, which results in the contamination of food products such as meat or dairy products, raw produce and processed foods. Important sources of foodborne outbreaks include contaminated dairy products such as soft cheeses, unpasteurized or improperly pasteurized milk and ice cream, hot dogs and delicatessen meats and raw produce, including packaged salads, cantaloupe and sprouts.

Invasive listeriosis usually affects pregnant women and their newborns, adults aged 65 and older and individuals with weakened immune systems (immunocompromised). Medical risk factors for invasive listeriosis include hematologic malignancy, organ transplantation, HIV infection or AIDS, alcoholism and liver and kidney disease. In the United States, L. monocytogenes accounts for ~5% of all cases of bacterial meningitis in infants <2 months of age and ~10% of all cases of bacterial meningitis in people ≥65 years of age. Invasive listeriosis occurs very infrequently in young, healthy adults. Overall rates of invasive listeriosis in the United States have remained relatively constant over the past decade (~3 cases per million population), as measured where active surveillance for listeriosis has been conducted.

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

The differential diagnosis of listeriosis includes all causes of meningitis or sepsis in newborn infants, such as group B streptococcus infection; all causes of meningitis and encephalitis in older adults and in individuals with weakened immune systems; and all causes of febrile illness during pregnancy, including viral syndromes.


Locked In Syndrome

Individuals with locked-in syndrome classically cannot consciously or voluntarily chew, swallow, breathe, speak, or produce any movements other than those involving the eyes or eyelids. Some affected individuals can move their eyes up and down (vertically), but not side-to-side (horizontally). Affected individuals are bedridden and completely reliant on caregivers. Despite physical paralysis, cognitive function is unaffected.

Locked-in syndrome is most often caused by damage to a specific part of the brainstem known as the pons. The pons contains important neuronal pathways between the cerebrum, spinal cord and cerebellum. In locked-in syndrome there is an interruption of all the motor fibers running from grey matter in the brain via the spinal cord to the body’s muscles and also damage to the centers in the brainstem important for facial control and speaking.

Locked-in syndrome is a rare neurological disorder that affects males and females in equal numbers. Locked-in syndrome can affect individuals of all ages including children, but most often is seen in adults who are more at risk for brain stroke and bleeding. Because cases of locked-in syndrome may go unrecognized or misdiagnosed, it is difficult to determine the actual number of individuals who have had the disorder in the general population.

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

A diagnosis of locked-in syndrome is usually made clinically. A variety of tests may be performed to rule out other conditions. Such tests include magnetic resonance imaging (MRI), which shows the damage to the pons, and magnetic resonance angiography, which can show the blood clot in the arteries of the brainstem. These tests can also rule out damage elsewhere in the brain.


Loeys-Dietz syndrome

LDS is a disorder of connective tissue, so it affects the bones, ligaments, arterial walls, and skin most significantly. A patient may not have all of the findings listed here, or maybe just one or two of the findings and still have the disease.

About 1/3 of individuals with LDS have an affected parent, while 2/3 of cases are caused by new or de novo pathogenic gene variants (mutations). These variants may then be passed down to children in an autosomal dominant manner. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The non-working abnormal gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.

LDS is a rare disorder that affects males and females in equal numbers. The prevalence of LDS is unknown though with more availability of genetic testing the number of patients diagnosed has increased significantly in recent years. The condition occurs in all ethnic groups.

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with significant clinical overlap with LDS including aortic root aneurysm, pectus (chest wall) deformities, scoliosis and arachnodactyly. However, individuals with LDS more often have widely spaced eyes, cleft palate/bifid uvula, craniosynostosis and/or club feet.  Individuals with LDS also have aneurysms more throughout the arterial tree, where those with MFS are most often at the root of the aorta.  Individuals with MFS are more likely to have eye lens dislocations and heart valve problems. MFS is caused by pathogenic variants in the FBN1 gene. (For more information on this disorder, choose Marfan syndrome as your search term on the Rare Disease Database.

The diagnosis of LDS is based on clinical suspicion and molecular confirmation through genetic testing to look for pathogenic variants in the causal genes: TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB, and TGFB3. Genetic testing should be considered in patients with typical signs/symptoms described previously and in families with known histories of thoracic aortic aneurysms. Cleft palate/bifid uvula, widely spaced eyes, translucent skin, arthritis and/or arterial tortuosity or aneurysm should prompt a physician to consider testing for LDS.

There is no known cure for LDS, but there are treatments directed at specific symptoms. These treatments typically require a team of specialists including a geneticist, cardiologist, heart (cardiothoracic) and bone (orthopedic) surgeons, rheumatologist, among others.


Long QT Syndrome

Long QT syndrome (LQTS) is an autosomal dominant disorder, caused by abnormalities of the heart’s electrical conduction system, and is characterized on the electrocardiogram (a test that records the electrical activity of the heart) by prolongation of the QT interval that corresponds to prolongation of the recovery phase or repolarization of the heart muscle (ventricular myocardium) after each heartbeat. QT prolongation predisposes those affected to an increased risk of life threatening sudden alterations in the cardiac rhythm, (termed arrhythmias), specifically torsade de pointes (TdP) or ventricular fibrillation (VF). These arrhythmias can lead to sudden loss of consciousness (syncope), cardiac arrest and potentially cause sudden cardiac death. The severity of cardiac symptoms varies greatly from one person to another, even among family members who carry the same rare genetic variant. Some individuals may have no apparent symptoms (asymptomatic) for their entire lives, whilst others develop arrhythmias resulting in episodes of syncope, and cardiac arrest, at a young age. Several different factors are known to trigger the onset of symptoms including physical activity, excitement and fright, although cardiac events may occur while asleep or at rest.

Symptoms, including syncope, can occur at any age from the newborn period to middle age, but most often appear during the pre-teen years through the 20s. Generally, the severity and frequency of episodes decreases during middle age and symptoms are less common after the age of 40 years. Approximately 50% of individuals, who have a mutation in one of the 15 genes that predispose to the disorder, ultimately develop symptoms; the others remain asymptomatic.

Long QT syndrome affects males and females in equal numbers and has been identified in all ethnic groups. The exact incidence and prevalence of the disorder is not known. It is estimated to occur in approximately 1 in 2,000 live births from a clinical and genetic study of 44,500 newborns (neonates).

The symptoms of LQTS can overlap with many other conditions.

The diagnosis of long QT syndrome is a clinical one, based upon a thorough evaluation, a detailed patient and family history and a specialized test called an electrocardiogram (ECG or EKG). Individuals with unexplained history of fainting, syncope, atypical epilepsy or sudden cardiac arrest should be evaluated for Long QT syndrome. An ECG records electrical activity of the heart and may reveal abnormal electrical patterns. The ECG may be abnormal at rest, both in terms of QT interval prolongation and T-wave morphology (shape).  As the penetrance of LQTS is low, many patients may have a relatively normal ECG at rest but the QT interval and morphological changes can be brought out either by standing or during the recovery period from exercise.

Treatment is aimed at preventing symptoms such as syncope or cardiac arrest. Specific medications, avoidance of triggering events and QT prolonging medication, and certain medical devices may all be used to treat individuals with Long QT syndrome. Genetic counseling is of great benefit for affected individuals and their families to understand implications for family members, recurrence risk, family planning options, and psychological adjustment to disease and/or carrier status.


良性复发性肝内胆汁淤积2型

Benign recurrent intrahepatic cholestasis type 2

Low Gamma-GT Familial Intrahepatic Cholestasis

benign recurrent intrahepatic cholestasis types 1 and 2

Low gamma-GT (GGT) familial intrahepatic cholestasis refers to a spectrum of disease, ranging from mild to severe cases. This spectrum of disease predominantly affects the liver. Advancements in understanding of bile transport physiology have led to the discovery of a variety of protein defects whose dysfunction leads to low GGT familial intrahepatic cholestasis. Children with defects in bile acid synthesis or conjugation, children with abnormalities of cell organization manifest as arthrogryposis-renal dysfunction-cholestasis syndrome, and children with neonatal hemochromatosis all may have low GGT familial intrahepatic cholestasis. These disorders are not covered in this report.

The age of onset, severity and specific symptoms of low GGT familial intrahepatic cholestasis may vary from one individual to another, even among members of the same family. Although these disorders are generally described as being either mild or severe, cases have been identified that appear to fall in between these extremes (intermediate types), leading researchers to classify these disorders as a spectrum of disease. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals or parents of affected children should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.

PFIC1 (FIC1 deficiency) occurs due to disruptions or changes (mutations) in ATP8B1, a gene that encodes a protein that is thought to be involved in maintaining differences in composition among different portions of cell membranes. Its function has been proposed to permit the secretion and transport of bile acids from the liver to the digestive tract. It is expressed not only in the liver, but other areas of the body as well, where its function permits other transporter proteins to work correctly. Its absence or dysfunction thus leads to problems like pancreatic inflammation and loss of hearing.

Low GGT familial intrahepatic cholestasis affects males and females in equal numbers. The exact incidence is unknown, but these disorders are extremely rare. However, because particularly in their milder forms these disorders often go unrecognized or misdiagnosed, they may be under-diagnosed, making it difficult to determine their true frequency in the general population.

Symptoms of the following disorders can be similar to those of low GGT familial intrahepatic cholestasis. Comparisons may be useful for a differential diagnosis:

Neonatal cholestasis refers to impaired flow of bile at any point from the liver cells into the intestine of a newborn. Neonatal cholestasis may be caused by viruses, metabolic disease or genetic disorders, as well as other rare diseases that affect or impair the function of the liver. In a small percent of patients, the cause of liver injury is unknown – these cases are referred to as idiopathic neonatal hepatitis (INH). The incidence of neonatal cholestasis is estimated to be ~1:2500 live births worldwide, and 25% to 50% are now known to be associated with changes (mutations) in specific genes. (For more information on this disorder, choose neonatal cholestasis as your search term in the Rare Disease Database.)


Oculocerebrorenal syndrome of Lowe

Lowe syndrome is characterized by vision problems including clouding of the lenses of the eyes (cataracts) that are present at birth, kidney problems that usually develop in the first year of life, and brain abnormalities that are associated with intellectual disabilities. Lowe syndrome is inherited as an X-linked genetic condition.

Boys with Lowe syndrome have cataracts that are present at birth in each eye (and detectable by high resolution ultrasound prenatally in suspect cases). With only extremely rare exceptions, these require surgery early in life, as soon as health allows for anesthesia to perform it. But even in optimal circumstances, corrected visual acuities when recordable are rarely better than 20/100. Approximately half of eyes will develop high pressure in the eye (glaucoma) that can damage the optic nerve and lead to blindness if not controlled. Infants with Lowe syndrome have poor muscle tone (hypotonia) at birth and experience delayed motor development. Almost all boys with Lowe syndrome have developmental and intellectual disability that can range from mild (~10%-25%) to severe (~50%-65%). Seizures occur in approximately half of those by six years of age, and behavioral problems are present in some boys with Lowe syndrome. A fraction of affected males develop growths on the corneas of one or both eyes called keloids during late childhood and adolescence. These growths are progressive and can lead to blindness.

Lowe syndrome is an X-linked genetic disorder caused by a mutation in the OCRL gene that results in reduced activity of the phosphatidylinositol polyphosphate 5-phosphatase OCRL enzyme. About a third of affected males have a new mutation in the gene; in most of the rest, the disorder is inherited from a mother who is a genetic carrier of the condition.

Lowe syndrome is a rare genetic disorder that occurs almost exclusively in males. The prevalence is estimated to be between 1 and 10 males per 1,000,000 people. This condition has been reported in North and South America, Europe, Japan, and India.

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

Congenital rubella (German measles) is a syndrome that occurs when a fetus has been infected with the rubella virus while in the uterus. It is primarily characterized by abnormalities of the heart and nervous system, the eyes, and the ears. The fetus is most vulnerable to the virus during the first three months of pregnancy, although pregnant women are advised to avoid exposure to rubella virus at all times. Women who contract rubella during pregnancy have a high risk of having a baby with congenital rubella. (For more information on this disorder, choose rubella, congenital as your search term in the Rare Disease Database.)


Lymphangioleiomyomatosis

The symptoms of LAM vary depending on the organs affected.

LAM is associated with the rare genetic disorder known as tuberous sclerosis complex (TSC) as both diseases are caused by changes (mutations) in one of two genes known as the TSC1 gene or TSC2 gene. There are two main types of LAM: sporadic LAM (called S-LAM that may occur without TSC) and LAM associated with TSC (called TSC-LAM). In both cases, abnormal LAM cells circulate in blood and lymphatic vessels and deposit in the lungs, causing cysts and lung damage. In S-LAM, mutations are thought to be somatic mutations (e.g., mutations that occur in peripheral tissues after conception and are not inherited). These mutations are not found in the blood or the normal lung or normal kidney cells of affected individuals. On the contrary, in TSC-LAM, these mutations may occur spontaneously (sporadically) for unknown reasons or be inherited in an autosomal dominant pattern. Most cases represent new (sporadic) gene mutations, with no family history of the disease.

LAM is a rare disorder that is estimated to affect approximately 3.4-7.8/1,000,000 women worldwide. The US LAM clinic network follows ~1,500 patients with LAM and there are ~3,000 patients with LAM registered with The LAM Foundation. Current estimates suggest that there are roughly 8,000–21,000 patients with sporadic LAM and 80,000–160,000 patients with TSC-LAM worldwide. However, many researchers believe that the disorder is under-diagnosed making it difficult to determine the true frequency in the general population.

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

There are several obstructive lung diseases that can cause symptoms that are similar to LAM, such as emphysema, asthma and chronic obstructive pulmonary disease (COPD). In addition, one third of women with LAM have shortness of breath that is relieved by bronchodilators, just like in asthma, which often causes diagnostic delay. Fortunately, these other obstructive lung diseases can be ruled out with laboratory tests and radiographic (x-ray) studies.


Macrocystic lymphatic malformation

Generally, symptoms from lymphatic malformations arise from compression or obstruction of nearby structures. Lymphatic malformations can involve any tissue. Usually they are found in only one area of the body (localized), but occasionally can be widespread (diffuse). When lymphatic malformations are widespread in bone and soft tissue, the condition may be referred to as lymphangiomatosis. Lymphatic malformations usually slowly grow larger as the patient grows, but sometimes get smaller spontaneously. Certain events such as puberty, infection, trauma or bleeding into a lymphatic malformation can cause them to grow rapidly.

The exact cause of lymphatic malformations is unknown. Lymphatic malformations result from abnormalities in the development of the lymphatic vascular system during embryonic growth. In a large number of patients, the lymphatic malformations have an activating mutation in the PIK3CA gene. This is a somatic (non-inherited) mutation isolated to the lymphatic endothelial cells lining the fluid filled channels. PIK3CA is known to play a role in regulating cell growth by signaling through the PI3K/mTOR pathway. Five different point mutations in DNA from lymphatic malformation tissue have been identified. It is unclear, however, if mutations in the PIK3CA gene alone cause lymphatic malformations. Sometimes the term PROS (PIK3CA-related overgrowth syndrome) is used to describe instances when both a PIK3CA mutation has been detected and overgrowth of the affected area is present.

Lymphatic malformations affect males and females in equal numbers. Most lymphatic malformations are evident at birth or within two years of age. However, in some patients, lymphatic malformations may not become apparent until adulthood. The exact prevalence of lymphatic malformations in the general population is unknown, but is thought to be approximately 1:4000 live births.

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

A diagnosis of lymphatic malformation can often be made before birth (prenatally) using ultrasound. An ultrasound is an exam that uses high-frequency sound waves to produce an image of the developing fetus. After birth, a diagnosis of a lymphatic malformation is made based upon a physical examination along with a detailed patient history.


Lymphedema-Distichiasis Syndrome

Lymphedema-distichiasis syndrome is a rare genetic multisystem disorder characterized by swelling of the legs because of fluid accumulation and the development of extra eyelashes (distichiasis). Distichiasis may range from a few extra lashes to a full set of extra eyelashes. Swelling most often affects both legs (bilateral) and usually occurs around puberty. Additional anomalies sometimes associated with this disorder include early onset varicose veins, droopy eyelids (ptosis), heart defects, cleft palate, abnormal heart rhythm and abnormal curvature of the spine (scoliosis). Lymphedema-distichiasis syndrome is caused by changes (pathogenic variants) of the FOXC2 gene and is inherited in an autosomal dominant pattern.

The symptoms of lymphedema-distichiasis vary greatly from person to person even among members of the same family. The most common finding is the extra row of eyelashes (distichiasis). Most patients also develop swelling (edema) or puffiness of the legs because of the accumulation of protein-rich fluid (lymph) in the soft layers of tissue under the skin.

Lymphedema-distichiasis syndrome occurs due to variants that disrupt/change the forkhead family transcription factor (FOXC2) gene. It is currently unknown exactly how variants in this gene lead to the symptoms of lymphedema-distichiasis syndrome, but the variants are thought to result in loss-of-function.

Lymphedema-distichiasis affects males and females in equal numbers. Lymphedema develops in males at an earlier age than females. The prevalence of this disorder in the general population is unknown. Lymphedema-distichiasis syndrome may go undiagnosed making it difficult to determine its true frequency in the general population.

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

A diagnosis of lymphedema-distichiasis syndrome is primarily made based upon a thorough clinical evaluation, a detailed patient history and the identification of characteristic findings (i.e., primary lymphedema, distichiasis). FOXC2 molecular testing is available clinically to help confirm a diagnosis. A variety of specialized tests may be performed to determine the extent of the disorder. Such tests include lymphoscintigraphy or an echocardiogram. During lymphoscintigraphy, a substance known as a contrast medium is injected into a lymphatic vessel (usually in a hand or foot). A series of x-rays are taken that show the medium as it moves through the lymphatic vessels giving physicians a picture of the health and structure of the lymphatic vessels. During an echocardiogram, reflected sounds waves are used to create an image of the heart, which can reveal congenital heart defects potentially associated with lymphedema-distichiasis syndrome.


Lymphocytic Infiltrate of Jessner

皮肤Jessner淋巴细胞浸润症

benign lymphocytic infiltrate of the skin

Patients living with lymphocytic infiltrate of Jessner may experience symptoms including itchiness  (pruritus), redness of the skin (erythema), and pimple-like eruptions (papules), most commonly on areas exposed to sunlight. These pimple-like lesions may last up to several months. As they extend from the perimeter, these lesions form well-defined, smooth, red patches (plaques) whose diameter may go as far as up to one inch.

Lymphocytic Infiltrate of Jessner is a rare inflammatory disease with an unknown cause. What is known however is that this condition involves the inappropriate accumulation of T helper cells (subtype of white blood cells) in the skin. Some clinical scientists argue that this condition is possibly a subtype of the autoimmune condition known as lupus erythematosus, while others believe that it may have its own class.

While its prevalence in the United States or Europe is not clearly understood as of yet, some scientists believe that lymphocytic Infiltrate of Jessner occurs predominantly in males. In addition, its onset usually occurs between the ages of thirty and fifty and rarely affects children.

Symptoms common in those living with Jessner’s lymphocytic infiltrate of the skin may also be found in other skin-related disorders. These include lymphocytoma cutis, mycosis fungoides, discoid lupus erythematosus; lupus erythematosus tumidus (LET), leprosy, polymorphous light eruption (PMLE), cutaneous lymphoid hyperplasia, granuloma annulare, and granuloma faciale. In some patients, it may be difficult to differentiate between Jessner’s lymphocytic infiltrate of the skin and the others mentioned above.

First, a thorough medical history and physical examination should be completed to assess for all potential risk factors including genetics and photosensitivity. In addition, a skin biopsy from a newly formed lesion should be tested in order to rule out other similar conditions including discoid lupus erythematosus (DLE) and polymorphous light eruption (PLE).


Lymphomatoid granulomatosis

benign lymph angiitis and granulomatosis

Lymphomatoid granulomatosis is a rare disorder characterized by overproduction (proliferation) of white blood cells called lymphocytes (lymphoproliferative disorder). The abnormal cells infiltrate and accumulate (form lesions or nodules) within tissues. The lesions or nodules damage or destroy the blood vessels within these tissues. The lungs are most commonly affected in lymphomatoid granulomatosis. Symptoms often include cough, shortness of breath (dyspnea) and chest tightness. Other areas of the body such as the skin, central nervous system, kidneys and liver are also frequently affected.

The symptoms and progression of lymphomatoid granulomatosis vary greatly from person to person. The disorder may occasionally resolve without treatment (spontaneous remission) in some affected individuals or more commonly it will progress and cause life-threatening complications. Occasionally, it is an incidental and asymptomatic finding on chest radiographs.

The exact cause of lymphomatoid granulomatosis is unknown. Lymphomatoid granulomatosis occurs with greater frequency in individuals with some form of immune system dysfunction including individuals with human immunodeficiency virus (HIV) infection and Wiskott-Aldrich syndrome. In most patients the cause of the immune dysfunction is unknown.

Lymphomatoid granulomatosis affects males twice as often as females. It is most common in middle-age adults in the fourth to sixth decade of life, but can occur at any age and has been reported in children. The prevalence of lymphomatoid granulomatosis is unknown.

Churg-Strauss syndrome is a rare disorder that may affect multiple organ systems, especially the lungs. The disorder is characterized by the abnormal clustering of certain white blood cells (hypereosinophilia) in the blood and tissues, inflammation of blood vessels (vasculitis), and the development of inflammatory nodular lesions called granulomas (granulomatosis). Most affected individuals have a history of allergy. In addition, asthma and other associated lung (pulmonary) abnormalities (i.e., pulmonary infiltrates) often precede the development of the generalized (systemic) symptoms and findings seen in Churg-Strauss syndrome by as little as six months or as much as two decades. Asthma, a chronic respiratory disorder, is characterized by inflammation and narrowing of the lungs’ airways, causing difficulties breathing (dyspnea), coughing, the production of a high-pitched whistling sound while breathing (wheezing), and/or other symptoms and findings. Nonspecific findings associated with Churg-Strauss syndrome typically include flu-like symptoms, such as fever, a general feeling of weakness and fatigue (malaise), loss of appetite (anorexia), weight loss, and muscle pain (myalgia). Additional symptoms and findings may vary depending upon the specific organ systems involved. The nerves outside the central nervous system (peripheral nerves), kidneys, or gastrointestinal tract are often involved. Without appropriate treatment, serious organ damage and potentially life-threatening complications may result. Although the exact cause of Churg-Strauss syndrome is unknown, many researchers indicate that abnormal functioning of the immune system plays an important role. (For more information, choose Churg Strauss as a search term in the Rare Disease Database.)

A diagnosis of lymphomatoid granulomatosis is made based upon a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests such as the surgical removal and microscopic examination (biopsy) of tissue samples taken from an affected organ such as the lungs. A skin biopsy is not reliable because the characteristic abnormal cells may be missing.


Lysosomal Free Sialic Acid Storage Disorders

The symptoms and severity of FSASD are highly variable. Some individuals will develop severe, life-threatening complications; others will have milder findings. The more severely affected patients usually exhibit symptoms within six months of birth or even before birth; milder cases may become apparent later during infancy or childhood. Affected individuals may not have all the symptoms discussed below.

FSASD is caused by changes (variants) in the SLC17A5 gene. The SLC17A5 gene contains instructions for producing (encoding) a protein called sialin that is required to transport free sialic acid out of lysosomes and into the cytosol of cells. Sialic acid is a charged sugar produced when lysosomes break down certain sugar-containing proteins (glycoproteins), carbohydrates or fats (glycolipids). In sialic acid storage disorders, deficient levels of functioning sialin result in the accumulation (storage) of free sialic acid in lysosomes.

FSASD affect males and females in equal numbers. The worldwide prevalence of FSASD is estimated at less than 1 per 1,000,000 individuals. Higher estimated prevalence rates occur in the Salla region of Finland and in other Scandinavian countries.

Signs and symptoms of the disorders mentioned below can be similar to those of FSASD. Comparisons may be useful for a differential diagnosis.

A diagnosis of a FSASD may be suspected based upon identification of characteristic signs and symptoms and by performing a thorough clinical evaluation, a detailed patient history (including family history) and specialized tests that detect elevated levels of free sialic acid in certain cells and tissues or in urine.


Lysosomal Storage Disorders

Lysosomal storage diseases are inherited metabolic diseases that are characterized by an abnormal build-up of various toxic materials in the body’s cells as a result of enzyme deficiencies. There are nearly 50 of these disorders altogether, and they may affect different parts of the body, including the skeleton, brain, skin, heart, and central nervous system. New lysosomal storage disorders continue to be identified. While clinical trials are in progress on possible treatments for some of these diseases, there is currently no approved treatment for many lysosomal storage diseases.

Although the signs and symptoms vary from disease to disease in this group, symptoms occur in each case because of an enzyme deficiency that inhibits the ability of the lysosomes present in each of the body’s cells to perform their normal function.  The lysosomes function as the primary digestive units within cells.  Their function is to break down complex components into simpler ones.  Each cell has hundreds of lysosomes that degrade complex cellular components such as proteins (substrates) into simpler components.  When this process does not take place, the substrate begins to accumulate in the cells.  That is why these diseases are called storage diseases.  The symptoms of lysosomal storage disorders are generally progressive over a period of time.

In each case, lysosomal storage diseases are caused by an inborn error of metabolism that results in the absence or deficiency of an enzyme, leading to the inappropriate storage of material in various cells of the body.  Most lysosomal storage disorders are inherited in an autosomal recessive manner.

As a group, lysosomal storage diseases are believed to have an estimated frequency of about one in every 5,000 live births.  Although the individual diseases are rare, the group together affects many people around the world.  Some of the diseases have a higher incidence in certain populations.  For instance, Gaucher and Tay-Sachs diseases are more prevalent among the Ashkenazi Jewish population.  A mutation associated with Hurler syndrome is known to occur more frequently among Scandinavian and Russian peoples.

Prenatal diagnosis is possible for all lysosomal storage disorders. Early detection of lysosomal storage diseases, whether before birth or as soon as possible afterward, is important because when therapies are available, either for the disease itself or for associated symptoms, they may significantly limit the long-term course and impact of the disease.


Spinocerebellar ataxia type 3

Autosomal Dominant Spinocerebellar Degeneration

Machado-Joseph Disease (MJD-III), also called spinocerebellar ataxia type III, is a rare, inherited, ataxia (lack of muscular control) affecting the central nervous system and characterized by the slow degeneration of particular areas of the brain called the hindbrain. Patients with MJD may eventually become crippled and/or paralyzed but their intellect remains intact. The onset of symptoms of MJD varies from early teens to late adulthood.

The symptoms of MJD Type I present between the ages of 10 and 30 years and progress rapidly. They may include severe weakness in the arms and legs (dystonia), spasticity or muscle rigidity, (hypertonia), awkward body movements (ataxia) often involving a slow, staggering, lurching gait (athetosis) that may be mistaken for drunkenness, slurred speech and swallowing (dysarthria), and possible damage to the muscles that control eye movements (ophthalmoplegia) and bulging eyes (exophthalmia).  Mental alertness and intellectual capacities are unaffected.

The gene responsible for MJD has been identified and mapped to Gene Map Locus; 14q24.3-q31.  This gene is associated with an abnormal number of CAG trinucleotide repeats (sometimes called triplets) in the DNA.  (CAG refers to the Cytosine-Adenine-Guanine trinucleotide structure.) Normal DNA usually has between 12 and 43 copies of the CAG trinucleotide.  In persons with the disease, the DNA contains from 56-86 copies of this trinucleotide.  Severity of symptoms and age of onset are related directly to the number of the repeats.  Thus, MJD-I will have fewer of these triplets while MJD-III will have the greater number.  The number of the CAG triplets found in the DNA of patients with MJD-II lies between the two extremes.

MJD is a rare inherited neurological disorder that disproportionately affects individuals of Portuguese descent, especially those from the Azores, an island colonized by Portuguese people.  MJD appears to affect slightly more males than females.

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

Hallervorden-Spatz Disease is a rare inherited disorder characterized by neurological degeneration.  Symptoms may include slow, steady muscle contractions of the arms, legs, neck, face, mouth, or trunk.  Other symptoms may include muscle spasms, slurred speech (dysarthria), mental retardation, impaired speech (dysphasia), and the loss of muscle mass (amyotrophy).  (For more information on this disorder choose Hallervorden-Spatz as your search term on the Rare Disease Database.)


Macroglossia

Macroglossia is the abnormal enlargement of the tongue. In rare cases, macroglossia occurs as an isolated finding that is present at birth (congenital). In many cases, macroglossia may occur secondary to a primary disorder that may be either congenital (e.g., Down syndrome or Beckwith-Wiedemann syndrome) or acquired (e.g., as a result of trauma or malignancy). Symptoms and physical findings associated with macroglossia may include noisy, high-pitched breathing (stridor), snoring, and/or feeding difficulties. In some cases, the tongue may protrude from the mouth. When inherited, macroglossia is transmitted as an autosomal dominant genetic trait.

Macroglossia is a disorder characterized by a tongue that is large in proportion to other structures in the mouth.  In the congenital type of the disorder, protrusion of the tongue from the mouth may interfere with feeding of the infant.  Later, talking may be affected.  The large size of the tongue may also cause abnormal development of the jaw and teeth, resulting in misaligned or protruding teeth.  Ulceration and dying tissue on the tip of the tongue may be other symptoms of the disorder.

Macroglossia may be found in individuals affected by certain inherited or congenital disorders including Beckwith-Wiedemann syndrome, acromegaly, primary amyloidosis, congenital hypothyroidism, Down syndrome, Apert syndrome, and many others.

Isolated autosomal dominant macroglossia is very rare, with about 50 cases reported in the medical literature.  The prevalence in other instances depends on the underlying disorder for which the macroglossia is secondary.  For example, macroglossia occurs in most cases of Beckwith-Wiedemann syndrome, and the prevalence of that syndrome is estimated at 1 in 17,000 births.

Macroglossia may be an early sign of Acromegaly.

Infants born with isolated autosomal dominant macroglossia present with the obvious sign at birth. A family history and physical exam can confirm the diagnosis.


Multiple symmetric lipomatosis

Madelung’s disease is characterized by the presence of fatty tumors (lipomas) located symmetrically around the neck, shoulders, trunk, hips, upper arms and thighs. While these abnormal fatty tumors may grow over the course of months to years, the disease usually has a rapid progression at first and then slows down as the size of the fatty mass stabilizes. The rest of the body may be lean in contrast to the affected parts.

The exact cause of Madelung’s disease is not fully understood. The body’s inability to properly metabolize fat indicates that it may be an endocrine disorder. One theory is that a defect in the adrenergic (epinephrine or norepinephrine)-stimulated fat breakdown (lipolysis) process results in improper deposition of fat. Alcohol can also negatively impact the enzymatic processes in mitochondria (energy-supplying part of the cell) and can alter adrenergic lipolysis in the body. Radial red fibers in the muscles of Madelung’s patients have often been found, indicating a sign of impaired mitochondrial respiratory chain function. Some researchers have noted that the distribution and type of fat cells in the fatty tumors is similar to the brown fat found in infants. Linking this to the theory, one study suggested that the fatty tumors formed in Madelung’s disease result from impaired mitochondrial regulation in the brown fat, causing increased division of fat cells (adipocyte hyperplasia). While current research suggests adrenergic pathways and mitochondrial dysfunction to be implicated in Madelung’s disease, a clear picture of the pathogenesis is yet to be determined.

Madelung’s disease most frequently affects males between 30-70 years of age. The condition is most common in people who consume excessive amounts of alcohol (especially red wine), for a long period of time. However, this disease has also been diagnosed in females and persons who do not consume alcohol. For reasons that are unclear, the disorder appears to be more prevalent in Mediterranean and European population as compared to North American and Asian population.

The differential diagnosis for Madelung’s disease includes lipomas, liposarcoma, lymphatic tumor, sialadenitis, neurofibromatosis, drug-induced lipomatosis (steroidal and antiretroviral drugs), angiolipoma and hibernoma. Some of these diseases are briefly described below:

The diagnosis of Madelung’s disease is based on a good clinical history, careful assessment of the appearance of the patient and imaging tests such as ultrasound, computerized tomography (CT)-scan or magnetic resonance imaging (MRI). Imaging tests can allow physicians to recognize the extent of fat deposition in the affected areas, appreciate compression of deeper structures and assess the presence of blood vessels in the fatty tumors. Imaging tests can also help rule out other diagnoses and provide insight for pre-operative surgical planning. Most patients come in with a complaint about their appearance due to the cosmetic deformity associated with Madelung’s disease. The diagnosis can be challenging in cases where the patient is obese from other factors (sedentary lifestyle, poor diet, etc.).


Maffucci syndrome

Maffucci syndrome is an extremely rare disorder characterized by benign cartilage overgrowths (enchondromas), skeletal deformities and cutaneous lesions composed of abnormal blood vessels. Enchondromas arise in bones, most frequently in the hands and feet, and less often in the legs and long bones of the arm.

Maffucci syndrome is not recognizable at birth. Lesions usually develop early in childhood, most often between 1-5 years of age. The severity of the disorder is variable. Some patients have a very benign course, whereas others develop serious complications.

In 2011, the cause of Maffucci syndrome was discovered to be a change (variant or mutation) in a gene known as IDH1 (rarely IDH2). The same gene variants are found in the related disorder Ollier disease. Since the variant occurs after fertilization (called a somatic mutation), Maffucci syndrome is not thought to be hereditary, that is, it cannot be passed along in a family. The cases occur randomly and there are no known families with multiple affected family members.

Maffucci syndrome occurs in all ethnic groups and equally affects males and females.

The following disorders can look similar to Maffucci syndrome; however, they usually can be differentiated by clinical examination.

The diagnosis of Maffucci syndrome is made by a detailed history, thorough physical examination and radiologic assessment. Surgical removal and microscopic study of the skeletal lesions confirm the presence of enchondroma and distinguish the tumor from chondrosarcoma.


Mal de Debarquemen

Mal de debarquement (MDD) is a rare and poorly understood disorder of the vestibular system that results in a phantom perception of self- motion typically described as rocking, bobbing or swaying. The symptoms tend to be exacerbated when a patient is not moving, for example, when sleeping or standing still. Studies have shown that a brief period of these symptoms is common in healthy individuals after prolonged episodes of passive motion, normally lasting seconds to three days. However, in MDD, significant balance impairment can persist for months to years. Symptoms may diminish in time or may reappear spontaneously or after another exposure. The most common triggers are water-based activities such as ocean cruising. Less common triggers include airplane travel, extended landing travel and sleeping on water beds. Other common complaints of patients with MDD include a sensation of uneven ground below their feet while walking, or feeling as if they are still on a boat. It is rare for MDD patients to have true rotational vertigo or motion sickness.

The primary symptom is the persistence of a sense of motion and rocking. Some patients may experience fatigue, mood changes and confusion. Imbalance is a common complaint. Symptoms often increase when exposed to fast movements, flickering lights and grocery store aisles. There may be transient improvement in symptoms with re-exposure to passive motion, for example, riding in cars or trains. After completion of the trip, however, the symptoms tend to recur.

The true cause behind MDD is still unknown. MDD likely results from the body’s balance system inadequately processing and adapting to multiple sensory inputs (visual, vestibular, proprioceptive and cognitive) from the environment once the stimulus (trigger) has ended. It is as yet undetermined as to the cause of the balance system’s inability to appropriately compensate and adapt. How or why this happens remains a mystery.

The majority of people affected are adult females, although there have been reports of males having the diagnosis. Patients with migraine may have any increased susceptibility through unknown mechanisms.

Benign paroxysmal positional vertigo (BPPV) is a common cause of dizziness, especially among the elderly. It comes about as a result of a movement of the head. Under normal conditions, calcium particles are attached to a specific location within the inner ear. As a result of injury or degeneration, these calcium particles clump together causing a sudden and brief episode of dizziness. (For more information on this disorder, choose BPPV as your search term in the Rare Disease Database.)

The diagnosis of MDD still remains mostly clinical. As such, the history is very important. Persistent dizziness after an ocean cruise, a sailing trip, a prolonged airplane flight or a cross-country road trip is highly suggestive of MDD. Vestibular function tests in patients with MDD have been normal or nonspecific in their abnormality. These tests are important in excluding other etiologies for the patient’s symptoms.


Malan Syndrome

Malan过度生长综合征

Symptoms of Malan syndrome generally appear in infancy. Most symptoms are related to a child’s size or developmental milestones. Malan syndrome is reported to have variable expressivity. Variable expressivity means that there is a range of symptoms that can occur in people affected with the same genetic condition.

Malan syndrome is caused by genetic changes (pathogenic variants) in the nuclear factor I X (NFIX) gene. Genes are the body’s instruction manual for creating proteins that play critical roles in how the body grows and develops properly. When a pathogenic variant in a gene occurs, it causes the protein to stop working. Depending on the function of the protein, it can affect many parts of the body. The NFIX gene encodes for a transcription factor and is important for brain, muscle, and bone development and differentiation. Transcription factors turn specific genes ‘on’ and ‘off’ in the body. Pathogenic variants in the NFIX gene cause this transcription factor to be partially unavailable for the body to use (haploinsufficiency), and as a result, other genes in the body do not know when to properly turn ‘on’ or ‘off.’ The transcription factor is needed for normal development, and when not working properly leads to the signs and symptoms of Malan syndrome. Malan syndrome can also be caused by microdeletions in the region of chromosome 19 where the NFIX gene is located (19p13.2).

There are approximately 300 individuals worldwide who have a diagnosis of Malan syndrome, making this an exceptionally rare diagnosis. Malan syndrome affects males and females equally and does not occur more frequently in any specific ethnic group. As of 2023, the oldest person living with Malan syndrome is 60 years old.

Symptoms of the following genetic disorders can be similar to those of Malan syndrome.

A thorough evaluation by a clinical geneticist is necessary to accurately diagnose Malan syndrome. Genetic testing is the primary method of diagnosis. Exome or NFIX sanger sequencing can be used to read the letters of the genetic code to look for pathogenic changes in the NFIX gene. Another genetic test that may be ordered is a chromosome microarray, which is a test that looks for extra or missing pieces of the genetic code. Individuals who have a partial or completely missing copy of the NFIX gene are also affected with Malan syndrome.

There currently is no cure for Malan syndrome and treatment is focused on the management of the medical problems that are present. Treatment and management is often coordinated by a neurologist. Seizures can be treated with antiepileptic drugs.


Malaria

Malaria is a communicable parasitic disorder spread through the bite of the Anopheles mosquito. Major symptoms may vary depending on which species of parasite causes the infection and the stage of development of the parasite. Chills and fever commonly occur, although not every case follows the same pattern.  Although the disorder was once thought to be under control throughout the world, malaria is a widespread infection especially in the tropics where certain types of mosquitos are becoming resistant to pesticides. The annual number of cases reported in the United States has increased in recent years.

Symptoms of malaria vary depending on which of the four parasite species is the cause.  Severity of symptoms may differ as the parasite goes through three different stages of development in humans.  It is possible to contract more than one kind of malaria at a time.  Symptoms may begin a week after exposure to the mosquito or may show up months later, even with preventive treatment.

Malaria is most commonly transmitted through the bite of the female Anopheles mosquito which is infected by a malaria parasite (Plasmodium).  Plasmodium Falciparum, Plasmodium Ovale, Plasmodium Malariae and Plasmodium Vivax are the four species of the parasite which can affect humans.  Additionally, transfusion of blood from an infected donor, or sharing contaminated needles may transmit the infection from one person to another.  In very rare cases, the disorder has been transmitted from an infected mother to a fetus.

According to the Centers for Disease Control and Prevention (CDC) in Atlanta, malaria is uncommon in the United States where approximately 1,200 cases are diagnosed each year, usually having been contracted abroad.  In the United States, malaria results in two to five deaths, on the average, each year.  Most cases in the U.S. occur among travelers, immigrants, and refugees.

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

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


Malignant Hyperthermia

Malignant hyperthermia (MH) is a dominantly inherited disorder of skeletal muscle that predisposes susceptible individuals to a life threatening adverse reaction (fulminant MH event) upon exposure to potent volatile anesthetics (halothane, isoflurane, sevoflurane, desflurane, etc.) and the skeletal muscle relaxant succinylcholine.

A fulminant MH episode is characterized by hypermetabolism that produces heat (hypethermia), increased oxygen uptake, and carbon dioxide production, along with hyperkalemia, and acidosis with hyperlacactemia.  Skeletal muscle rigidity may either be localized to the masseter muscle or generalized.  Muscle damage is reflected by increases in serum creatine kinase, potassium, calcium, and phosphate.  Rhabdomyolysis with myoglobinuria and myoglobinemia often occurs.  The time of onset after induction of general anesthesia may vary from minutes to hours, and patients may have had previously uneventful exposure to anesthetics.

The MH phenotype is inherited as an autosomal-dominant trait with incomplete penetrance and variable expression.  Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease.  The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual.  The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy.  The risk is the same for males and females.

The incidence of MH during general anesthesia is estimated at 1/4,200 (suspicion of MH) to 1/250,000 (fulminant MH). Published reports probably underestimate the true incidence because of the difficulty in defining mild MH events.  In the past decade, two independent studies have estimated the incidence of RYR1 variants in the general population as 1 in 2,000 to 1 in 3,000 persons.   More recent exome studies suggest that the frequency of RYR1 variants may be higher than that.6

MH has been associated with other myopathies such as central core disease (CCD), multiminicore disease (MMD), and nemaline rod myopathy, as well as exertional rhabdomyolysis (ER) and exertional heat illness (EHI).

Many individuals with MH are otherwise unaffected. Thus, identifying these individuals before they are given general anesthesia is difficult. Family history of the disorder is important, as is the history of any adverse metabolic responses to anesthesia. Definitive diagnosis of MH susceptibility is made by in vitro contracture test performed on biopsied leg muscle. These tests are based on the differential contractile response of normal and MH muscle to halothane and caffeine. In North America, the test is the caffeine halothane contracture test (CHCT), and in Europe the test is the in vitro contracture test (IVCT). Both tests are invasive, requiring a muscle biopsy, and can only be performed in specialized MH diagnostic centers.


Mandibuloacral dysplasia

The signs and symptoms of mandibuloacral dysplasia can vary from one person to another. The age of onset of certain symptoms can vary as well. Children with mandibuloacral dysplasia type A often develop normally for the first 4 to 5 years of life. Children with mandibuloacral dysplasia type B can develop noticeable symptoms of the disorder by the age of 2. Mandibuloacral dysplasia type B has only been described in a handful of children. Common symptoms associated with both forms of the disorder have been characterized, but, because of the low number of identified cases, it is difficult to get an accurate picture of associated symptoms and prognosis.

Mandibuloacral dysplasia type A is caused by mutations of the LMNA gene; type B is caused by mutations of the ZMPSTE24 gene. Some individuals with mandibuloacral dysplasia do not have mutations of either gene    suggesting that additional, as-yet-unidentified genes may also cause the disorder.

Approximately 40 cases of mandibuloacral dysplasia have been reported in the medical literature. Fewer than 10 cases of mandibuloacral dysplasia type B have been reported in the medical literature. Many cases of the disorder most likely go misdiagnosed or undiagnosed, making it difficult to determine the true frequency of mandibuloacral dysplasia in the general population.

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

A diagnosis of mandibuloacral dysplasia is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests.


Mantle Cell Lymphoma

Many individuals with mantle cell lymphoma may not have symptoms (asymptomatic) during early stages of the disease. However, affected individuals may eventually seek medical attention due to persistent, usually painless, swelling of certain lymph nodes, particularly nodes within the neck and throat region (e.g., Waldeyer’s ring). Waldeyer’s ring consists of the protective ring of lymphoid tissues near the base of the tongue (lingual tonsils); on either side of the throat (palantine tonsils); and near the back opening of the nasal cavity (pharyngeal tonsils or adenoids). Individuals with non-Hodgkin’s lymphomas (NHLs), including MCL, may also have enlargement of other lymph nodes, such as nodes at the elbows or shoulders; under the arms (axillae); in the chest, abdominal, and/or pelvic regions; and/or in other areas. Lymph node enlargement may be confined to a single region or be present in various areas of the body.

The exact underlying cause of mantle cell lymphoma is unknown. As with numerous types of cancer, there are many possible factors that may contribute to its development. These factors include genetic and immunologic abnormalities, environmental factors (e.g., exposure to ultraviolet rays, certain chemicals, ionizing radiation [carcinogens]; certain viral infections; etc.), diet, stress and others. Current investigations are researching the possibility of an association between family history, inflammation, infection and the development of MCL.

Mantle cell lymphoma is an uncommon form of non-Hodgkin’s lymphoma (NHL), accounting for 5% to 7% of all cases of NHL. Approximately one out of 200,000 individuals is diagnosed each year with MCL. The disease primarily affects older adults, with males representing approximately three-quarters of those with MCL. Many affected individuals are diagnosed at approximately 60 to 70 years old. Reports suggest that most individuals with MCL have advanced (i.e., stage III or stage IV) disease at diagnosis.

Symptoms of the following conditions may be similar to those of mantle cell lymphoma (MCL). Comparisons may be useful for a differential diagnosis:

Hodgkin’s disease and non-Hodgkin’s lymphoma (NHL) are the two major types of cancer affecting the lymphatic system (lymphoma). In contrast to NHL, Hodgkin’s disease is typically characterized by the presence of a specific type of cancer cell known as a Reed-Sternberg cell that has more than one nucleus. The disease is categorized into several subtypes according to certain features of affected lymphatic tissue as seen under a microscope (microscopic examination), such as relative number of Reed-Sternberg cells, proportion of other types of white blood cells, certain tissue changes, etc. (For further information, choose Hodgkin as your search term in the Rare Disease Database.)


Maple syrup urine disease

The symptoms and severity of MSUD varies greatly from patient to patient and largely depends upon the amount of residual enzyme activity.

MSUD is caused by changes (mutations) in one of three different genes: BCKDHA, BCKDHB and DBT. Mutations in these genes result in absent or decreased activity of human branched-chain alpha-ketoacid dehydrogenase complex (BCKAD) enzymes. These enzymes are responsible for breaking down the branched chain amino acids leucine, isoleucine, and valine that are in all proteins. Accumulation of these amino acids and their toxic byproducts (ketoacids) results in the serious health problems associated with MSUD. The toxicity of these amino acids is restricted to leucine; indeed, extra valine and isoleucine are often given during treatment. Accumulation of their respective ketoacids results in the metabolic acidosis.

The estimated incidence in a general population is 1 in 185,000 live births. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. Due to this founder effect, the disorder occurs with greater frequency among individuals in the Mennonite populations in the United States, where the incidence is estimated to be as high as in 1 in 380. MSUD occurs in the Ashkenazi Jewish population with an incidence estimated at 1:26,000 live births.

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

Many infants with MSUD are identified through newborn screening programs. Tandem mass spectrometry, an advanced newborn screening test that screens for more than 40 different disorders through one blood sample, has aided in the diagnosis of MSUD. As with all inborn errors, Infants with mild or intermittent forms of the disorder may have totally normal blood metabolites after birth and thus can be missed by newborn screening.


Marcus-Gunn syndrome

Marcus Gunn phenomenon is a rare genetic disorder that is usually present at birth. It is characterized by the movement of one upper eyelid in a rapid rising motion each time the jaw moves. Other eye abnormalities and vision difficulties may also occur. The exact cause of this phenomenon is not known.

In most patients with Marcus Gunn phenomenon, the upper eyelid of one eye (unilateral) droops (blepharoptosis).  The major symptom of this disorder is the rapid and involuntary upward movement of the affected eyelid after almost any movement of the lower jaw.  As a result, that eye appears to open even wider.  This first becomes apparent soon after birth, especially during feeding and sucking. These activities cause the eyelid to move up and down.  A few cases have been seen in adults.

The exact cause of Marcus Gunn phenomenon is not known.  For reasons that are unclear, there is a bad connection between the nerves that stimulate, and the muscles that move, the eyelids and the jaw.  Some clinical researchers believe that about half of the cases of Marcus Gunn phenomenon are genetically determined.  The site and nature of the gene(s) at fault in this disorder are not known, but familial studies indicate that it is transmitted as an autosomal dominant trait.

Marcus Gunn phenomenon is a rare genetic disorder present at birth.  It affects males and females in equal numbers.  Approximately 300 cases have been reported in the medical literature.

Marcus Gunn Phenomenon may occur in conjunction with certain other eye disorders such as Duane Syndrome, or possibly Retinitis Pigmentosa.  (For more information on these disorders, choose Duane, or Retinitis Pigmentosa as your search term in the Rare Disease Database.)

The diagnosis is obvious and is often made by one or both of the parents who become aware of the major symptom during feeding.


Marden Walker Syndrome

Connective Tissue Disorder, Marden-Walker Type

Marden-Walker syndrome is a rare connective tissue disorder that is inherited as an autosomal recessive trait. Patients with this disorder typically have a distinct facial expression, a cleft or high-arched palate, small or receding jaw (micrognathia), bone joints in a fixed position, growth delay and limited control of muscle movement. Marden-Walker syndrome affects males more often than females.

Patients with Marden-Walker syndrome have distinct facial features including an abnormality of the jaw, droopy eyelids, a flat bridge of the nose, low-set ears, and a fixed facial position.

Marden-Walker syndrome is inherited as an autosomal recessive trait.  The exact genetic malfunction is not yet established but some clinicians believe a single gene defect may be responsible.

Marden-Walker Syndrome is a very rare disorder that affects males more often than females with a ratio of 11 to 3.  There have been approximately twenty cases reported in the medical literature.

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

Van den Ende-Gupta syndrome (VDEGS) is a Marden-Walker-like disorder in which many of the skeletal symptoms of Marden-Walker syndrome are present.  (For more information on this disorder, see the Online Mendelian Inheritance in Man or OMIM database, entry 600920.)

Genetic counseling may be of benefit for patients and their families. Other treatment is symptomatic and supportive.


Marfan syndrome

Marfan syndrome is a genetic disorder that affects connective tissue, which is the material between cells of the body that gives the tissues form and strength. Connective tissue is found all over the body and multiple organ systems may be affected in individuals with Marfan syndrome. The heart and blood vessels (cardiovascular), skeletal, and eye (ocular) systems are most often affected. Major symptoms include overgrowth of the long bones of the arms and legs, abnormal side-to-side curvature of the spine (scoliosis), indentation or protrusion of the chest wall (pectus deformity), dislocation of the lenses of the eyes (ectopia lentis), nearsightedness (myopia), widening (aneurysm) and tear (dissection) of the main artery that carries blood away from the heart (aorta), floppiness of the mitral valve (mitral valve prolapse) and backward flow of blood through the aortic and mitral valves (aortic and mitral regurgitation). The specific symptoms and the severity of Marfan syndrome vary greatly from person to person. Marfan syndrome is inherited as an autosomal dominant trait, meaning that only one abnormal copy of the Marfan gene inherited from one parent is sufficient to have the condition. Defects or deletions (pathogenic variants) of the fibrillin-1 (FBN1) gene have been shown to cause Marfan syndrome.

The specific symptoms of Marfan syndrome vary greatly from person to person. Some individuals will develop only a few mild or isolated symptoms; others will develop more serious complications. In most cases, Marfan syndrome progresses as individuals grow older. In some infants, Marfan syndrome may cause severe, rapidly progressive complications during infancy, often quickly affecting multiple organ systems early in life. Marfan syndrome can potentially affect many systems of the body including the heart, blood vessels, skeleton, eyes, lungs, and skin.

Marfan syndrome is caused by defects or deletions (mutations) of the fibrillin-1 (FBN1) gene. Not everyone who has a mutation of this gene develops Marfan syndrome. Some changes do not alter the function of the gene or protein and therefore do not cause a medical problem. Other changes in the FBN1 gene can cause conditions that are distinct from Marfan syndrome.

Marfan syndrome affects males and females in equal numbers and occurs worldwide with no ethnic predisposition. The prevalence has been estimated to be 1 in 5-10,000 individuals in the general population. Because of the difficulty in diagnosing mild cases of Marfan syndrome, the disorder is probably underdiagnosed, making it difficult to determine its true frequency in the general population.

Symptoms of the following disorders can be similar to those of Marfan syndrome. Comparisons are essential to arrive at a correct diagnosis.

No universal, specific diagnostic test exists for Marfan syndrome despite the identification of the causative gene. A diagnosis is made based upon a detailed patient and family history, a thorough clinical evaluation, and a variety of specialized tests performed to identify key findings associated with Marfan syndrome. Different criteria have been proposed for classifying someone as having Marfan syndrome. The most recent published criteria (the revised Ghent nosology) were published in 2010. According to these guidelines, the presence of aortic root aneurysm, eye lens dislocation, or a family history of definite Marfan syndrome weigh heavily in the diagnosis of Marfan syndrome, with an additional potential contribution of other findings throughout the body. Molecular testing (e.g. looking for a mutation in the FBN1 gene) can aid in the diagnosis of Marfan syndrome, but identifying a mutation is not sufficient to establish the diagnosis in the absence of sufficient physical findings or family history.


Marinesco-Sjögren Syndrome

Marinesco-Sjögren syndrome (MSS) is a rare genetic disorder that affects multiple organ systems of the body. Common symptoms include difficulty coordinating voluntary movements due to degeneration (atrophy) of the cerebellum (cerebellar ataxia), clouding of the lenses of the eyes (cataracts), delays in the acquisition of skills requiring the coordination of muscular and mental activity (psychomotor development), diminished muscle tone (hypotonia), and progressive muscle weakness. Many affected individuals exhibit additional physical abnormalities. Although Marinesco-Sjögren syndrome can be associated with significant disability, lifespan is often unaffected. Marinesco-Sjögren syndrome is caused by mutations of the SIL1 gene and at least one other, presently unknown, gene.

Some symptoms of Marinesco-Sjögren syndrome are often present at birth (congenital) including diminished muscle tone (hypotonia), a condition sometimes referred to as floppy baby. Cataracts can also be present at birth, but more often develop rapidly during early childhood. Cataracts occur when the lenses of the eyes become clouded preventing light from being focused onto the retina and thereby affecting vision. In most cases, cataracts affect both eyes (bilateral).

Marinesco-Sjögren syndrome is often caused by mutation of the SIL1 gene. It 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.

Marinesco-Sjögren syndrome affects males and females in equal numbers. More than 200 cases have been reported in the medical literature. The exact incidence of the disorder in the general population is unknown. Marinesco-Sjögren syndrome can affect all ethnic groups (panethnic), but most cases have occurred in isolated populations in rural areas.

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

A diagnosis of Marinesco-Sjögren syndrome may be suspected based upon the identification of characteristic findings. A diagnosis can be confirmed by a thorough clinical evaluation, a detailed patient history and a variety of specialized tests including an eye (ophthalmologic) exam to detect cataracts and magnetic resonance imaging (MRI) to detect characteristic changes in the brain (e.g., cerebellar atrophy). Imaging studies of muscle may show significant damage to muscle tissue and the abnormal accumulation of fat and connective tissue.


Marshall Syndrome

deafness-myopia-cataract-saddle nose, Marshall type

Marshall syndrome is a rare autosomal dominant genetic disorder caused by mutations in the COL11A1 gene. Major symptoms may include a distinctive face with a flattened nasal bridge and nostrils that are tilted upward, widely spaced eyes, nearsightedness, cataracts and hearing loss.

Patients with Marshall Syndrome have a distinctive flat sunken midface with a flattened nasal bridge (saddle nose), nostrils that turn upward, and a wide space between the eyes (hypertelorism). The dome-like upper portion of the skull (calvaria) is thicker than normal and calcium deposits can be found in the skull (cranium).  Frontal sinuses may be absent. Eye defects found in patients with Marshall Syndrome are nearsightedness, a disease of the eye in which the lens loses its clarity (cataract), and a wide space between the eyes making the eyeballs appear to be larger than normal. Hearing loss may range from slight to severe; the distortion of the sound is a consequence of the nerve damage (sensorineural). Other symptoms exhibited by some patients with Marshall Syndrome are: crossed eyes (esotropia), a condition in which the line of vision is higher in one eye than the other (hypertropia), retinal detachment, glaucoma, protruding upper incisors (teeth) and a smaller than normal or missing nasal bone.

Marshall syndrome is a rare autosomal dominant genetic disorder caused by mutations in the collagen XI, alpha-1 polypeptide (COL11A1) gene located on chromosome 1p21.1. Typically mutations causing Marshall syndrome are splice site mutations involving base pair insertions or deletions of intron 50.  Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy.

Marshall Syndrome affects males and females in equal numbers.

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

Congenital spondyloepiphyseal dysplasia is a rare genetic disorder characterized by growth deficiency before birth (prenatally), spinal malformations, and/or abnormalities affecting the eyes. As affected individuals age, growth deficiency eventually results in short stature (dwarfism) due, in part, to a disproportionately short neck and trunk, and a hip deformity in which the thigh bone is angled toward the center of the body (coxa vara). In most cases, affected individuals may have diminished muscle tone (hypotonia), abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis), abnormal inward curvature of the spine (lumbar lordosis), and/or unusual protrusion of the breastbone (sternum), a condition known as pectus carinatum. Affected individuals also have abnormalities affecting the eyes including nearsightedness (myopia) and, in approximately 50 percent of cases, detachment of the nerve-rich membrane lining the eye (retina). Congenital spondyloepiphyseal dysplasia is inherited as an autosomal dominant trait, also linked to mutations, deletions, and duplications the COL2A1 gene, with autosomal dominant inheritance. (For more information on this disorder, choose spondyloepiphyseal dysplasia congenita as your search term in the Rare Disease Database.)

Plastic surgery can improve saddle nose in Marshall syndrome. Other surgical procedures are used to remove the lenses of eyes affected by cataracts, after which lens implants are used as replacements. Subsequently, contact lenses may help improve sharpness of vision. Laser techniques are used to loosen any material, such as the cornea or the lens capsule that may adhere to the lens. The use of a hearing aid may be beneficial in some cases. Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.


Marshall-Smith syndrome

Marshall-Smith syndrome (MSS) is largely characterized with faster than normal bone growth. Due to their taller stature, patients have low muscle tone, muscle weakness, and may experience difficulties in gaining weight. Patients with Marshall-Smith syndrome may also have abdominal hernias (umbilical hernias), intellectual developmental delays, psychomotor delays (slowing down of thought and voluntary movements), and/or breathing difficulties. The breathing difficulties can sound like a high-pitched noisy breath, due to abnormal neck extension, with the tongue blocking the airway. Some traits related to the windpipe of Marshall-Smith syndrome patients include the abnormal development of the leaf-shaped structure in the throat that stops foods and liquids from entering the windpipe. The nasal passages may be smaller, and these patients may have an abnormal larynx with soft cartilage. Patients with Marshall-Smith syndrome typically have a long head with a prominent forehead, prominent eyes, an upturned nose with a low nasal bridge, and excessive hair growth. The patient’s eye whites may appear bluish, and the lower jawbone may be smaller than average. Their fingertips may appear narrow while the rest of the finger may appear broad.

There are indications that Marshall-Smith syndrome is caused by a change (mutation) in the NFIX gene. This gene plays an important role in transcription initiation for various genes. In human embryonic development, expression of NFIX can be detected during brain and skeletal development. The most common variant types leading to Marshall Smith syndrome are frameshift and splice site variants. Most individuals with Marshall-Smith syndrome are the first individuals in their families to have this syndrome and as such they are de-novo cases.

Marshall-Smith Syndrome is a rare disorder that has only been documented in about 50 individuals worldwide. It appears to affect males and females equally. Symptoms are typically present at birth, such as the previously escribed characteristic facial features.

Weaver syndrome is similar to Marshall-Smith syndrome in that growth and bone ages faster than normal, or advanced bone age. Patients with both Weaver and Marshall-Smith syndromes tend to have their growth spurt early in age but will stop growing sooner compared to normal individuals. However, patients with Weaver syndrome are usually overweight, whereas patients with Marshall-Smith syndrome are underweight. There are several other distinguishing physical and behavioral characteristics between Marshall-Smith and Weaver syndrome. (For more information on this condition, search for Weaver in the Rare Disease Database.)

Patients with Marshall-Smith syndrome are diagnosed based on clinical findings and symptoms, as well as the use of x-ray exams to identify the skeletal indications. Genetic diagnosis can now be performed by looking for mutations in the NFIX gene.


Mastocytosis

Mastocytosis is a rare disorder characterized by abnormal accumulation and activation of mast cells in the skin, bone marrow and internal organs (liver, spleen, gastrointestinal tract and lymph nodes). Mastocytosis can affect both children and adults. Mastocytosis can be classified to a specific type depending on the patient’s symptoms and overall presentation. Cases beginning during adulthood tend to be chronic and involve the bone marrow in addition to the skin, whereas, during childhood, the condition is often marked by skin manifestations with no internal organ involvement and can often resolve during puberty. In adult patients, mastocytosis tends to be persistent, and may progress into a more advanced category in a minority of patients.

The severity of the symptoms associated with mastocytosis may vary from mild to life-threatening. In general, symptoms occurring in mastocytosis are mainly due to the release of chemicals from the mast cells and thus produce symptoms associated with an allergic reaction, although a true allergic trigger may not be identified. Flushing and gastric acid hypersecretion due to mast cell-associated histamine release are common symptoms. Heartburn, stomach aches, abdominal discomfort, bloating and diarrhea may occur. The liver, spleen and lymph nodes may become enlarged in advanced disease varieties; therefore regular follow-up is necessary. Bones affected by mastocytosis may become softened (osteoporosis) and deteriorate, although some new bone growth may occur with thickening of the outer portions or spongy inner areas of the bones. In aggressive systemic mastocytosis, a decrease in blood cells (cytopenia), break-down of bones (osteolysis), swelling of the lymph nodes (lymphadenopathy), swelling of the liver (hepatomegaly), impaired liver function, ascites or portal hypertension and malabsorption, may also occur.

Genetic alterations (mutations) resulting in the over-activation of the receptor for mast cell growth factor (KIT) have been identified in the abnormal mast cells in almost all patients with adult-onset mastocytosis and in skin lesions of approximately 80% of affected children. The most common KIT mutation in mastocytosis is D816V and is believed to cause the abnormal proliferation and accumulation of mast cells in tissues. Over 90% of adults and 40% of children also express this mutation whereas another 40% of children have mutations involving other areas of the KIT gene. It is not yet clear if the type of KIT mutation in children has value in predicting disease severity. The mutations are present in the body cells (somatic) of affected individuals, but not in egg and sperm cells (germline) in the majority of patients and, therefore, are not passed on to the next generation.

Mastocytosis affects males and females in equal numbers. It can begin during childhood or adulthood. Childhood-onset disease most commonly presents within the first year of life.

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