Myasthenia gravis

Myasthenia gravis is a neuromuscular disorder primarily characterized by muscle weakness and muscle fatigue. Although the disorder usually becomes apparent during adulthood, symptom onset may occur at any age. The condition may be restricted to certain muscle groups, particularly those of the eyes (ocular myasthenia), or may become more generalized (generalized myasthenia gravis), involving multiple muscle groups. Most individuals with myasthenia gravis develop weakness and drooping of the eyelids (ptosis); weakness of eye muscles, resulting in double vision (diplopia); and excessive muscle fatigue following activity. Additional features commonly include weakness of facial muscles; impaired speech (dysarthria); difficulties chewing and swallowing (dysphagia); and weakness of the upper arms and legs (proximal limb weakness). In addition, in about 10 percent of patients, affected individuals may develop potentially life-threatening complications due to severe involvement of muscles used during breathing (myasthenic crisis). Myasthenia gravis results from an abnormal immune reaction in which the body’s natural immune defenses (i.e., antibodies) inappropriately attack and gradually injure certain receptors in muscles that receive nerve impulses (antibody-mediated autoimmune response).

Symptoms may be variable, with disease involvement potentially localized to certain muscles or affecting multiple muscles. In some affected individuals, the disease process may be limited to certain eye muscles, which is often described as ocular myasthenia. In those with more generalized disease or generalized myasthenia gravis, affected muscles may include those of the eyes, face, jaw, and throat region; arm and leg (limb) muscles; and muscles involved in breathing (respiratory muscles).

Most individuals with myasthenia gravis (MG) have no family history of MG and the disorder appears to occur spontaneously (sporadically) for unknown reasons. However, upwards of 5 percent of patients may have family members with MG or other autoimmune disorders. Individuals with MG have an increased frequency of certain genetically determined human leukocyte antigens (HLAs), suggesting that genetic predisposition may play some role. (HLAs are proteins that play an important role in the body’s immune system; they influence the outcome of transplantation and appear to affect an individual’s predisposition to certain diseases.) Other autoimmune diseases also appear to occur with increased frequency in individuals with MG, including thyroid disorders and systemic lupus erythematosus. These observations suggest that there is some genetic predisposition to MG which requires a trigger from the environment to cause the disease.

Autoimmune myasthenia gravis has a prevalence of approximately 14-40 per 100,000 individuals in the United States. Reports indicate that the frequency of the disorder has appeared to increase over the last several decades. This may be because of better identification of patients, but also autoimmune disorders in general are increasing in frequency across the world.

Symptoms of the following disorders may be similar to those of myasthenia gravis (MG). Comparisons may be useful for a differential diagnosis:

Lambert-Eaton (myasthenic) syndrome is also known as Eaton-Lambert syndrome. It is a rare autoimmune disorder of adulthood in which antibodies abnormally attack certain proteins on the surface of nerve endings that regulate calcium levels (calcium channels), resulting in inadequate release of acetylcholine. It is characterized by muscle weakness and fatigue, particularly of the hip and thigh muscles. Additional symptoms and findings may include absence of certain reduced reflex responses and dysfunction of particular involuntary functions (autonomic symptoms), such as dryness of the mouth, constipation, impotence, and/or other abnormalities. Cancer, particularly certain types of lung cancer, is frequently associated with the disease. (For more information, choose Lambert-Eaton as your search term in the Rare Disease Database.)


Mycosis Fungoides

Mycosis fungoides is a rare form of T-cell lymphoma of the skin (cutaneous); the disease is typically slowly progressive and chronic. In individuals with mycosis fungoides, the skin becomes infiltrated with plaques and nodules that are composed of lymphocytes. In advanced cases, ulcerated tumors and infiltration of lymph nodes by diseased cells may occur. The disorder may spread to other parts of the body including the gastrointestinal system, liver, spleen, or brain.

STAGE I: The first sign of mycosis fungoides is usually generalized itching (pruritus), and pain in the affected area of the skin. Sleeplessness (insomnia) may also occur. Red (erythematous) patches scattered over the skin of the trunk and the extremities appear. These lesions may resemble other skin disorders such as psoriasis, parapsoriasis, lichen planus, or eczema.

The exact cause of mycosis fungoides is not known. Current theories include antigen persistence, retroviruses (e.g., HTLV-1, etc.), and exposure to cancer-causing (carcinogenic) substances.

Mycosis fungoides rarely occurs before age 40 years. It affects males twice as often as females.

Symptoms of the following skin disorders may resemble those of mycosis fungoides. Comparisons may be useful for a differential diagnosis:

A diagnosis of mycosis fungoides may be made by a thorough clinical evaluation and a variety of specialized techniques and tests including DNA cytophotometry, nuclear contour analysis, and analysis of T-cell receptor gene rearrangement.


Myelodysplastic Syndromes

The symptoms of MDS occur because the bone marrow fails to produce enough functioning blood cells. The specific symptoms and progression of the disorder vary greatly from person to person. Some individuals may have mild symptoms that remain stable for many years; others may rapidly develop serious symptoms that can progress to life-threatening complications.

When the cause of MDS is unknown it is called idiopathic MDS. A so-called secondary MDS can develop after chemotherapy and radiation treatment for cancer or autoimmune diseases. It is possible that some chemicals (pesticides and benzene), cigarette smoking, and possibly viral infections can predispose to MDS. However, these links are circumstantial and in the majority of individuals developing MDS no obvious connection with environmental hazards can be found. MDS sometimes runs in families, suggesting a genetic link with the disease, particularly in younger patients with this disease.

Myelodysplastic syndromes affect males slightly more often than females. The disorder occurs in any age group, but is far more common in older adults, occurring most often in individuals over 60 years of age. According to one estimate, 22 to 45 per 100,000 people over the age of 70 years have MDS. Approximately 20,000 new patients are diagnosed each year in the United States. The number of new cases diagnosed each year is increasing, possibly due to better recognition of the disorder combined with an increasing proportion of elderly adults in the general population. Determining the exact frequency of MDS in the general population is difficult because of lack of reporting of patients with mild cytopenias.

MDS shares features with other blood disorders which need to be considered before reaching the correct diagnosis.

A diagnosis of myelodysplastic syndrome is made based upon a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests including complete blood counts, examination of the blood smear and bone marrow aspiration and biopsy. A complete blood count measures the number of red and white blood cells and platelets in the body. The blood smear and the small sample of bone marrow removed via a needle (the aspirate) is examined under a microscope to evaluate for the characteristic features of MDS. Chromosome analysis is helpful for diagnostic and prognostic purposes as is a blood test determining the presence of certain mutations (changes) within the blood cells.


Myhre syndrome

laryngotracheal stenosis, arthropathy, prognathism, and short stature

Although researchers have been able to describe a recognizable syndrome with characteristic or core symptoms, much about the disorder is not fully understood. Several factors including the small number of identified patients and the lack of large clinical studies prevent physicians from developing a complete picture of associated symptoms and prognosis. No other genes have been identified to cause Myhre syndrome. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below and that every patient is unique. Parents of affected children and adults with Myhre syndrome should talk to their primary care physician and medical team about their specific case, associated symptoms and overall prognosis.

Myhre syndrome is caused by a gain-of-function mutation (pathogenic variant) in the SMAD4 gene. It is the only gene known to cause the disorder. Genes provide instructions for creating (encoding) proteins that play a critical role in many functions of the body. When a mutation occurs, the protein product of the gene may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.

Myhre syndrome is an extremely rare inherited disorder that, in theory, affects males and females in equal numbers. Fewer than 100 patients have been reported in the medical literature, but cases are being steadily published. Because some cases of Myhre syndrome most likely go undiagnosed or misdiagnosed, determining the true frequency of the disorder in the general population is difficult.

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

There are other congenital disorders that may be characterized by intellectual disability and growth deficiency occurring in association with facial abnormalities, skeletal malformations, and/or other physical abnormalities similar to those associated with Myhre syndrome. Such disorders include, but are not limited to, GOMBO syndrome, acromicric dysplasia, geleophysic dysplasia, Weil-Marchesani syndrome, and acromesomelic dysplasia. However, none of these syndromes is identical to Myhre syndrome. The thickened skin associated with Myhre syndrome may resemble the stiffened skin seen in stiff skin syndrome. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)


Myoclonic-astatic epilepsy

MAE is a seizure disorder that begins in early childhood. Nearly all patients have their first seizures before the age of five, with 24% beginning before the child’s first birthday. Most children with MAE have normal development up to the time of diagnosis, though 20% have minor delays that often present with speech difficulties. For most patients, the first seizure is a generalized tonic-clonic seizure. Tonic refers to a stiffening stage, wherein the body becomes rigid. This can cause falls and loss of bladder control due to the inability to control muscle function. The tonic period usually lasts for less than thirty seconds before transitioning into the clonic phase, which involves the limb jerks and rapid movements that are characteristically associated with epileptic episodes. Throughout the duration of the episode, the child is completely unconscious and unaware of what is occurring, and may not regain consciousness until a few minutes afterwards.

The exact cause of MAE is unknown. Between 34-44% of patients have at least one family member with a history of epilepsy. Interestingly, the type of prior seizure disorder is not consistent among family members, but typically remains within the GEFS+ (genetic epilepsy with febrile seizures plus) spectrum. The GEFS+ family of seizures are characterized by seizures that are typically brought on by febrile or afebrile (non-fever induced) seizures and are recurrent. These cases must be seen among several family members throughout different generations in order to be classified as GEFS+ cases. The most frequent seizure types among those with GEFS+ include myoclonic, atonic, and absence seizures.

Myoclonic atonic epilepsy is a rare disorder that accounts for 1-2% of all epilepsy diagnoses. This translates to affecting less than 1 in every 100,000 children born each year. When the disorder presents before the first year of life, males are affected far more than females, in about a 3:1 ratio. However, when diagnosed after the first year of life, the gender ratio becomes nearly equal. One in four children experiences their onset seizure before their first birthday, and 94% of cases occur before the age of five. In one third of cases, the child has family members with a history of some form of epilepsy, typically within the GEFS+ (genetic epilepsies with febrile seizures plus) spectrum. Around 2% of children have family histories of myoclonic and atonic seizures specifically. While this may seem like a small percentage, it is 200 times greater than the correlation found among the general population.

Due to the significant overlaps in seizure types, ages of onset and symptoms experienced, there are many disorders that share similarities with myoclonic atonic epilepsy. The specific presence of myoclonic-atonic seizures are what set MAE apart from the other generalized seizure types. However, there are several other disorders that are considered to be differential diagnoses.

While there isn’t a genetic diagnosis for myoclonic atonic epilepsy, a combination of clinical symptoms and EEG findings are used for diagnosis. While patients with MAE may experience a variety of seizure types, the presence of myoclonic-atonic seizures is absolutely indicative of MAE. Additional findings typically include:


Myofibrillar myopathy

Myofibrillar myopathies are a group of rare genetic neuromuscular disorders that may be diagnosed in childhood but most often appear after 40 years of age. These conditions are highly variable but are characterized by a slowly progressive muscle weakness that can involve skeletal muscle (muscles that function to move bones) and smooth muscle (muscle often associated with organs, such as the digestive tract). Skeletal muscle weakness can be present in the limb muscles close to the center of the body (proximal) as well as the muscle farther from the center of the body (distal). A weakening of the heart muscle (cardiomyopathy) is common and may result in an irregular heartbeat (arrhythmia or conduction defects) or congestive heart failure.

Specific signs and symptoms of myofibrillar myopathies vary by subtype, which are defined by the causative gene (see below). However, all involve progressive muscle weakness and characteristic abnormalities in muscle cells (myofibrillar disorganization and protein accumulation). Some people with myofibrillar myopathy have muscle stiffness, aching, cramps or decreased muscle mass (atrophy). Cardiomyopathy is sometimes the first symptom and may present as arrhythmia, conduction defects or congestive heart failure.

Myofibrillar myopathies may be caused by disease-causing mutations in a single gene or by many changes in multiple genes in combination with environmental factors. Genes function as the instructions for the creation of proteins, and the disease-causing mutations result in excess amounts of a particular protein in muscle. The genes responsible for myofibrillar myopathies are identified in approximately 20% of affected individuals. These disorders have been categorized by the gene involved.

The frequency of myofibrillar myopathies is not well understood. It is likely that these conditions are unrecognized and underdiagnosed.

Signs and symptoms of the following muscle disorders may be similar to those of myofibrillar myopathies. Comparisons may be useful for a differential diagnosis:

Myotonic dystrophy type 1 (DM1) is an autosomal dominant, multi-system disorder that affects both smooth and skeletal muscles and may affect the central nervous system, heart, eyes and/or endocrine systems. Classic DM1 is characterized by muscle weakness and atrophy, cataracts, myotonia (impaired muscle relaxation) and abnormalities in the heart’s conduction of electrical impulses. Myotonic dystrophy type 2 (DM2), is an autosomal dominant disorder with symptoms that are similar to DM1, but tend to be milder and more variable than DM1. (For more information on this disorder, choose myotonic dystrophy as your search term in the Rare Disease Database.)


Myopathy, Scapuloperoneal

X连锁遗传性肩胛腓骨部肌营养不良

Scapuloperoneal myopathy is a rare genetic disorder characterized by weakness and wasting of certain muscles. Symptoms are usually limited to the shoulder blade area (scapula) and the smaller of the two leg muscle groups below the knee (peroneal). Facial muscles may be affected in a few cases. The leg symptoms often appear before the shoulder muscles become weakened. The rate of progression of the disorder varies from case to case. This condition can also occur in combination with other disorders. Scapuloperoneal myopathy is inherited as an autosomal dominant trait.

Symptoms of scapuloperoneal myopathy primarily include muscle weakness and wasting usually limited to muscles in the shoulder blade and girdle area and the legs below the knees. This disorder can begin in childhood or adulthood. The progression rate and severity may vary greatly, with some cases progressing more quickly than others. In most cases, the progression is slow.

Scapuloperoneal myopathy is inherited as an autosomal dominant trait. Human traits including the classic genetic diseases, are the product of the interaction of two genes for that condition, one received from the father and one from the mother.

Scapuloperoneal myopathy affects males and females in equal numbers. Symptoms may begin in childhood or during adulthood. Scapuloperoneal myopathy is a rare disorder; the exact prevalence of this disorder in the general population is unknown.

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

Scapuloperoneal amyotrophy (also known as Kaeser syndrome or scapuloperoneal syndrome, neurogenic type) is characterized by muscle weakness and wasting (atrophy) below the knees accompanied by foot abnormalities and an unusual walk. Eventually, the shoulder muscles may also become involved. Nerve impulses may become measurably slowed, which does not occur in scapuloperoneal myopathy. Pain, unusual sensations in the legs, heart problems, and muscle contractures may also occur. Scapuloperoneal amyotrophy is inherited as an autosomal dominant trait.

There is no specific treatment for individuals with scapuloperoneal myopathy. Treatment may include specified amounts of therapeutic exercise and physical therapy alternating with periods of rest.


Thomsen and Becker disease

Myotonia congenita is a rare genetic disorder in which an abnormality of voluntary (skeletal) muscle fiber membranes causes an unusually exaggerated response to stimulation (hyperexcitability). As a result, affected individuals have difficulty relaxing certain muscles after contracting them (myotonia), muscle stiffness (rigidity), and associated symptoms. Such symptoms tend to occur when attempting to move certain muscles after rest. In many cases, individuals with myotonia congenita also have abnormal enlargement of the muscles (hypertrophy), resulting in a herculean or body-builder like appearance.

Myotonia congenita is a disorder of voluntary (skeletal) muscle characterized by an exaggerated response to stimulation of certain muscle fibers (hyperexcitability). As a result, there is painless spasm (tonic spasm) of affected muscle after forceful voluntary contraction, abnormal muscle stiffness, and difficulty relaxing muscle (myotonia). Such symptoms tend to occur when affected individuals attempt to move certain muscles following a period of inactivity or when affected muscles are mechanically stimulated. Characteristic symptoms may include difficulties relaxing hand grip; completely opening the eyes after forcibly closing them (e.g., following crying or sneezing); arising from a chair; starting to walk or run; climbing stairs; and/or arising from bed at night. As noted above, the myotonia is characteristically most pronounced following a period of rest. In addition, it typically improves by gradually increasing the force or intensity of movements through warming up. Most individuals with myotonia congenita also develop abnormal enlargement of voluntary muscles (hypertrophy), resulting in an athletic appearance.

Thomsen type myotonia congenita is transmitted as an autosomal dominant trait. Genetic diseases are determined by two genes, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the 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 regardless of the sex of the resulting child.

Thomsen and Becker types myotonia congenita are thought to affect males and females in relatively equal numbers. Reported cases have included multiple affected members in multigenerational families (kindreds) as well as apparently sporadic cases. The reported incidence of these disorders is between .3 and .6 per 100,000 people in the general population.

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

Paramyotonia congenita is a rare genetic nonprogressive disorder that usually becomes apparent during infancy. The disorder is often characterized by myotonia triggered or aggravated by exposure to cold and alleviated by warm temperatures; in addition, the myotonia is sometimes described as paradoxic, since it tends to become more severe rather than to improve with exercise. Some with the disorder may also be affected by episodes of weakness or partial paralysis (paresis) that do not necessarily coincide with exposure to cold temperatures or myotonia. In addition, in some cases, periods of weakness may be induced by the administration of potassium. The disorder is not associated with muscle wasting or hypertrophy. Paramyotonia congenita is a sodium channel disease (sodium channelopathy). It results from mutations of a gene (called SCN4A) that has also been linked to hyperkalemic periodic paralysis (see below). The disease gene has been mapped to the long arm (q) of chromosome 17. Paramyotonia congenita is transmitted as an autosomal dominant trait. (For more information on this disorder, choose paramyotonia congenita as your search term in the Rare Disease Database.)


Myotonic Dystrophy

The signs and symptoms of DM1 or DM2 can vary greatly among affected individuals. This is true even among members of the same family. Many people will not develop all of the symptoms discussed below. Every person is unique and how these disorders affect a person can be very different. In addition, DM1 and DM2 have many symptoms that overlap, but there are also symptoms unique to each disorder, clearly marking them distinct disorders.

DM1 is caused by a change or alteration in the myotonic dystrophy protein kinase (DMPK) gene. DM2 is caused by a change or alteration in the nucleic acid-binding protein (CNBP) gene; this gene is also called the ZNF9 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.

DM1 is estimated to affect about 1 in 8,000-20,000 people in the general population. However, the prevalence of DM1 and DM2 vary greatly among different countries and different ethnic groups. The incidence of DM2 is higher in Germany and Finland. Because some people with DM may go unrecognized or undiagnosed, determining the true frequency of these disorders in the general population is difficult. Researchers have determined that DM is the most common form of adult onset muscular dystrophy.

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

A diagnosis of myotonic dystrophy may be suspected based upon a thorough clinical evaluation, a detailed patient and family history, and identification of characteristic physical findings. A family history of muscle weakness and myotonia is a strong indicator of a diagnosis for DM.

There is no cure yet for myotonic dystrophy, but researchers are studying ways to help people with these disorders. Current treatment is directed toward the specific symptoms that are apparent in each individual.


N-乙酰谷氨酸合成酶缺乏所致高氨血症

Hyperammonemia due to N-acetylglutamate synthase deficiency

hyperammonemia due to N-acetylglutamate synthetase deficiency

NAGS deficiency may be associated with complete or partial absence of the NAGS enzyme. Complete lack of the NAGS enzyme results in the severe form of the disorder, in which symptoms occur shortly after birth (neonatal period). Partial lack of the NAGS enzyme results in a milder form of the disorder that occurs later during infancy or childhood or even adulthood in some cases. Specific symptoms can vary from one person to another.

NAGS deficiency is an autosomal recessive genetic disorder caused by mutations of the NAGS gene. Mutations in the NAGS gene results in deficiency of the enzyme N-acetylglutamate synthetase. The symptoms of NAGS deficiency develop due to the lack of this enzyme which is needed to break down nitrogen in the body. Failure to properly break down nitrogen leads to the abnormal accumulation of nitrogen, in the form of ammonia, in the blood (hyperammonemia). Specifically, the NAGS enzyme is an activator of another enzyme of the urea cycle known as carbamyl phosphate synthetase (CPS).

NAGS deficiency is a rare disorder that affects males and females in equal numbers. In most cases, onset of symptoms occurs at, or shortly following, birth. The estimated frequency of urea cycle disorders collectively is one in 30,000 births. However, because urea cycle disorders like NAGS deficiency often go unrecognized, these disorders are under-diagnosed, making it difficult to determine the true frequency of urea cycle disorders in the general population.

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

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


Nager syndrome

The specific symptoms that occur may vary from one person to another, even among members of the same family. Affected individuals may develop a variety of craniofacial and limb abnormalities which usually are noticeable at birth (congenital).

Most cases of Nager syndrome are cause by mutations in the SF3B4 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.

Nager syndrome affects males and females in equal numbers. The exact incidence and prevalence in the general population is unknown. Many cases go misdiagnosed or undiagnosed, making it difficult to determine the true frequency in the general population. More than 100 cases have been reported in the medical literature. Although rare, Nager syndrome is the most common form of acrofacial dysostosis.

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

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


Nail Patella Syndrome

Nail changes are the most constant feature of NPS (98%). In most individuals with NPS, improper development (dysplasia) of the nails is apparent at birth or early infancy. While the thumbnails are almost always affected, the other fingernails may be more mildly affected or not at all. Typically the severity of the nail dysplasia decreases from the thumb toward the 5th digit. The nails may be abnormally small and narrow (i.e., one half to one third of normal size), split, abnormally thickened, depressed, and/or discolored. In addition, in most people, the crescent-shaped pale area at the base of the nail (lunula) is malformed and/or triangular. Improper development (dysplasia) of the toenails is usually less common than the fingernails; if the toenails are involved, it is often the little toenail that is affected.

NPS is an autosomal dominant genetic condition. Human traits, including the classic genetic diseases, are the product of the interaction of two copies of every gene. One copy is received from the father and one from the mother. 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 an affected individual to each offspring is 50% for each pregnancy. The risk is the same for males and females. Approximately 90% of people with NPS have an affected parent and, therefore, 10% develop the condition as the result of a new mutation.

NPS affects males and females in equal numbers and is thought to affect approximately one in 50,000 people. The true prevalence may be higher since mildly affected people may be undiagnosed.

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

Small patella syndrome is also known as ischiopatellar dysplasia or Scott-Taor syndrome. It is also a dominant condition and is caused by mutations in TBX4. It is characterized by absent or small patella, abnormal ossification (not fused) of the ischiopubic junction and a characteristic axe-cut notch below the acetabulum which can be seen by radiographs. Patients with small patella syndrome do not have abnormalities of their nails, elbows, eyes or kidneys.


Nance-Horan Syndrome

Nance-Horan syndrome is a rare genetic disorder that may be evident at birth (congenital). It is primarily characterized by abnormalities of the teeth and clouding of the lens of the eyes (congenital cataracts), resulting in poor vision. Additional eye (ocular) abnormalities are also often present, such as unusual smallness of the front, clear portion of the eye through which light passes (microcornea) and involuntary, rapid, rhythmic eye movements (nystagmus). In some affected individuals, the disorder may also be associated with additional physical abnormalities and/or intellectual impairment. The range and severity of symptoms may vary greatly from one person to another, including among affected members of the same family.

In affected males, the primary physical characteristic associated with Nance-Horan syndrome is the presence of dense clouding (opacities) of the lens of both eyes at birth (congenital bilateral nuclear cataracts).The lens of an eye is the small transparent flattened and elongated ball located behind the iris through which light passes. The light focuses on the retina, the thin nerve-rich membrane that lining the back of the eye. The retina converts the light into nerve impulses and relays the information along the optic nerve to the brain. Cataracts affect both eyes (bilateral) and usually result in blurred vision and severely decreased clearness or clarity of vision (visual acuity). Vision loss can potentially be profound.

Nance-Horan syndrome is caused by mutations of the NHS gene, which is located on the X chromosome. The function of this gene is not fully understood. Nance-Horan syndrome is inherited as an X-linked 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.

As discussed above, Nance-Horan syndrome is usually fully expressed in males only, although females who carry a single copy of the disease gene (heterozygotes) may develop certain features. The disorder is present at birth (congenital). Nance-Horan syndrome was described in 1974 by two research teams independent of each other. Fewer than 50 families (kindreds) have been described in the medical literature. The exact incidence of the disorder is unknown. Researchers believe that affected individuals may go unrecognized or misdiagnosed, making it difficult to determine the true frequency of Nance-Horan syndrome in the general population.

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

There are several other rare inherited disorders in which clouding of the lens of the eyes at or shortly after birth (congenital or postnatal cataracts) occurs in association with other abnormalities of the eye. In some cases, the front (anterior), clear portion of the eye through which light passes (cornea) may be unusually small and/or the entire eye may be smaller than normal (microphthalmia). In addition, affected individuals may exhibit rapid, involuntary movements of the eyes (nystagmus); nearsightedness (myopia); misaligned eyes (strabismus); and/or other abnormalities of the eyes. Visual impairment may range from slight to severe, depending upon the extent of cataracts and/or any additional eye abnormalities that are present. These rare cataract disorders are typically isolated and/or may be inherited as autosomal dominant, autosomal recessive, and/or X-linked genetic traits, depending upon the disorder in question. Such disorders include isolated microphthalmia with cataract; cataract-microcornea syndrome; X-linked congenital cataract (total congenital cataract with posterior sutural opacities in heterozygotes; and X-linked congenital cataract with microcornea. The latter two disorders are caused by mutations in the same gene that causes Nance-Horan syndrome (allelic disorders). Some researchers believe that these three disorders represent different expressions of one disorder.


Narcolepsy

The development and severity of symptoms associated with narcolepsy vary greatly from one person to another. The onset of symptoms initially occurs one at a time; appearance of new symptoms may be separated by years, with sleepiness generally preceding cataplexy. Narcolepsy usually begins in an adolescent whose initial symptoms are mild but worsen with age. Sometimes symptoms do not change for months, while at other times symptoms may change very quickly. Depending upon the severity of the disorder, narcolepsy can dramatically affect a person’s daily routine, disrupting all aspects of a person’s life.

Narcolepsy with cataplexy (type 1) has been linked to low levels of a specific brain chemical called hypocretin (also known as orexin). This chemical plays an important role in regulating sleep and other functions. Hypocretin also functions as a neurotransmitter, a chemical that modifies, amplifies or transmits nerve impulses from one nerve cell (neuron) to another, enabling nerve cells to communicate. Researchers have determined that the number of neurons that produce hypocretin is significantly reduced in individuals with narcolepsy. Hypocretin-producing neurons are found in the hypothalamus, the area of the brain that regulates many functions including sleep, appetite and body temperature. In some individuals as many as 80-90 percent of hypocretin-producing neurons in the hypothalamus are lost. Individuals who have narcolepsy with cataplexy have the lowest levels of hypocretin.

The exact number of people with narcolepsy in the United States is unknown. One estimate places the prevalence at .03 percent to .16 percent of the general population in various ethnic groups worldwide. One U.S. study placed the incidence of new cases of narcolepsy at .74 per 100,000 person-years in the general population in the United States. The disorder has also been estimated to affect 1 in 2,000 people in the general population. However, because narcolepsy often goes unrecognized or misdiagnosed, determining its true frequency in the general population is difficult.

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

Idiopathic hypersomnia is a rare condition characterized by episodes or extreme sleepiness that occur for no identifiable reason (idiopathic). Episodes may be chronic or constant. The disorder differs from narcolepsy in that affected individuals do not experience sudden sleep episodes or develop cataplexy. In addition, affected individuals do not feel refreshed after a nap. Some individuals with idiopathic hypersomnia sleep for long periods (e.g., more than 10 hours); others sleep for shorter periods (e.g., fewer than 10 hours). Idiopathic hypersomnia can disrupt many aspects of life. Behavioral modification and certain medications are used to treat the disorder.


Necrotizing Enterocolitis

Necrotizing enterocolitis, abbreviated NEC, is a devastating disease that affects a newborn’s intestines. It typically occurs in premature infants, born less than 37 weeks, and is characterized by severe inflammation of a baby’s small or large intestines, which may progress to tissue death (necrosis). NEC occurs in about 1 case per 1000 live births [1]. NEC can occur in full term babies but it is much more common in very premature infants, especially very low birth weight babies — incidence ranges from 3% in infants with birth weight of 1251 to 1500 grams (2 pounds 12.13 ounces to 3 pounds 4.91 ounces) to 11% for infants born weighing less than 750 grams (1 pounds 10.46 ounces) [2]. NEC typically occurs when a newborn is several weeks old and on enteral feeds. Initially babies present with vomiting, large distended belly, bloody stools, long pauses in their breathing, and decreased activity. This can further progress to bowel necrosis and perforation. Medical treatment involves discontinuation of enteral feeds (the delivery of nutritionally complete feeds directly into the stomach), initiation of broad-spectrum antibiotics and supportive care [3]. Surgical intervention is indicated when there is evidence of bowel perforation and necrotic bowel. This serious gastrointestinal disease is associated with significant morbidity (complications associated with the disease) and mortality. Despite treatment, about 15% of babies who develop NEC die and some babies that survive suffer from numerous complications such as short bowel syndrome, poor growth, and long-term neurodevelopmental impairments [4]. The exact mechanism of this disease, while not fully understood, is believed to be multifactorial and related to a premature intestine, abnormal gut microbial colonization, and intestinal inflammation.

Onset of NEC is typically during the first several weeks after birth when feeds have been started, and the age of onset inversely related to gestational age at birth. Early in the disease process, neonates can exhibit signs of feeding intolerance with vomiting, increased gastric aspirates, bile-tinged (green) gastric aspirates, or decreased bowel sounds with abdominal distention and tenderness. Gross or occult blood can be present in stools indicating mucosal injury. Many of these signs are non-specific and can occur with other disorders. Progression of NEC results in systemic signs such as lethargy, long pauses in breathing called apnea, temperature instability, and poor perfusion (pumping of fluid through an organ or tissue.) Ultimately this can lead to respiratory failure and cardiovascular collapse requiring mechanical ventilation and vasopressors. A palpable mass and erythema (abnormal redness of the skin due to capillary congestion, as in inflammation) of the abdominal wall is indicative of a more advanced disease process.

After many years of research and clinical observation, the etiology and pathogenesis of NEC remain elusive. Some key risk factors have been consistently identified as important prerequisites for initiation of intestinal injury leading to NEC. These include prematurity, formula feeding, abnormal microbial intestinal colonization, and ischemia (when blood vessels to the intestines become narrowed or blocked, reducing blood flow.) [3;10;11].

NEC affects 5 to 10% of premature infants born weighing less than 1500 g. Among the risk factors defined for NEC, prematurity and birth weight remain inversely related to risk for NEC. Term infants who develop NEC usually have specific risk factors such as congenital heart disease, sepsis, and low blood pressure.

Many other gastrointestinal diseases can mimic NEC, so when evaluating a patient it is important to consider and treat alternative etiologies. Sepsis can cause an ileus with abdominal distention and feeding intolerance. Premature infants, especially those on indomethacin or steroids can also present with spontaneous intestinal perforation (SIP). SIP is characterized by isolated perforation of the distal small bowel. Other causes of severe abdominal distention in neonates include bowel obstruction from Hirshsprung’s disease, small bowel atresia, meconium ileus, and malrotation with volvulus. NEC can also be mistaken for allergic enterocolitis secondary to cow’s milk protein allergy.

NEC is diagnosed clinically and radiographically. Once clinical suspicion arises, an abdominal X-ray is performed as an initial evaluation. This is repeated serially depending on acuity and clinical course to assess disease progression. Characteristic findings on NEC process on abdominal radiographs include pneumatosis intestinalis (air in the intestinal wall), abnormal persistent dilated loops, thickened bowel wall, pneumoperitoneum and portal vein gas. Pneumoperitoneum defined as abdominal free air is a surgical emergency indicating bowel perforation and usually requires intervention. Abdominal ultrasonography can also be used to evaluate for free fluid in the abdominal cavity or abscess formation. Addition laboratory studies to evaluate severity of NEC include a blood culture, coagulation studies and complete blood count with manual differential to assess for leukocytosis with bandemia, neutropenia, anemia and thrombocytopenia. Blood gases are checked serially to assess severity of acidosis and need for respiratory support or to assist with fluid management.

Treatment of NEC depends on the clinical staging. In cases of suspected NEC, stage I, initial treatment consists of bowel rest with discontinuation of enteral feeds, nasogastric decompression, cultures of blood, and initiation of broad-spectrum antibiotics. While infant remains NPO, nothing by mouth, intravenous parenteral nutrition is initiated. Close observation with serial examinations and radiographs is essential. Surgical consultation is obtained once NEC is confirmed, stage II or III. Supportive care includes respiratory support, inotropic (cardiac function) support, fluid resuscitation and correction of acid-base imbalance. Patients with NEC can develop disseminated intravascular coagulation (DIC) (a condition that prevents blood from clotting normally) from consumption of clotting factors and require blood product transfusions. The principal indication for surgical intervention in NEC is a perforated or necrotic intestine. Other indications include clinical deterioration and severe abdominal distention causing abdominal compartment syndrome (organ dysfunction or failure due to a severe increase in the pressure within the abdomen.) Two surgical approaches are usually done depending on clinical presentation, laparotomy with resection (removal) of necrotic bowel or primary peritoneal drainage (the procedure of inserting a Penrose drain into the space within the abdomen that contains the intestines, the stomach, and the liver).


Nelson Syndrome

corticotroph tumor progression after bilateral adrenalectomy

Major symptoms and signs of Nelson syndrome include the following:

Cushing disease is characterized by the presence of a non-cancerous tumor on the pituitary gland causing excessive production of ACTH. Nelson syndrome develops when the tumor in the pituitary gland grows after the removal of the adrenal glands (bilateral adrenalectomy). The adrenal glands normally produce cortisol. When no cortisol is produced, the hypothalamus signals the pituitary gland to produce adrenocorticotropic hormone (ACTH), which normally signals the adrenal glands to produce cortisol. Since the adrenal glands are removed, the pituitary gland continues to produce ACTH. This eventually leads to enlargement of the pituitary gland tumors or new growths.

Nelson syndrome is diagnosed more often in females than males (8:1), especially in middle-aged females who have Cushing disease. Of the small population (about 6 percent) of Cushing disease patients who have surgery to remove both adrenal glands, 15 to 25 percent develop Nelson syndrome one to four years after the procedure. However, the disorder can arise up to 24 years after the surgery. Current data indicates 21 percent of cases of Nelson syndrome occur within 5 years of a bilateral adrenalectomy.

Noncancerous pituitary tumors (adenomas) can appear like a Nelson syndrome tumor on medical imaging.

Nelson disease may be suspected when hyperpigmentation occurs in a patient who has had a bilateral adrenalectomy.

The first recommended step in treating Nelson syndrome is the removal of the tumor using surgery through the nasal passages (transsphenoidal surgery). Radiation therapy might be used after surgery. For some patients, frequent medical imaging may be recommended to monitor tumors instead of offering surgery. Because patients with Nelson syndrome are not able to produce cortisol and aldosterone, hydrocortisone and mineralocorticoids are required supplements. Additional therapies can be used to treat individual symptoms and provide pain relief. Recent studies have shown mixed results with drug therapies.


Nemaline myopathy

The age of onset and severity of symptoms and signs associated with nemaline myopathy vary greatly from patient to patient. Some patients with nemaline myopathy present at or shortly after birth (congenital onset). Less often, the disorder may develop during childhood or even more uncommonly in adulthood.

Ten genes have been found to cause nemaline myopathy. Nemaline myopathy can be inherited as an autosomal recessive or dominant trait. At least 50% of cases of nemaline myopathy follow autosomal recessive inheritance, and the remainder are inherited in an autosomal dominant manner or are sporadic (new dominant cases – the first occurrence in the family).

Nemaline myopathy is a rare disorder that affects males and females. The incidence is unknown although two studies (one in Finland and one in an American Ashkenazi Jewish population) estimated the incidence to be 1 in 50,000 live births. An incidence of 1/500 has been reported in the Amish community.

Congenital myopathy is a general term for a group of muscle disorders (myopathies) that are present at birth (congenital). These disorders are characterized by muscle weakness, hypotonia, diminished reflexes, and delays in reaching motor milestones (e.g., walking). In some disorders, muscle weakness is progressive and may result in life-threatening complications. This group of disorders includes central core disease, centronuclear myopathy, congenital fiber type disproportion, and minimulticore myopathy. Congenital myopathies are usually apparent in the newborn (neonatal) period, but may present much later in life even in adulthood. In most cases, inheritance of these disorders is either autosomal recessive or autosomal dominant. (For more information on this disorder, choose the specific disorder name as your search term in the Rare Disease Database.)

A diagnosis of nemaline myopathy is suspected based upon a thorough clinical evaluation, a detailed patient and family history and identification of characteristic findings. A diagnosis of nemaline myopathy is suspected based upon a thorough clinical evaluation, a detailed patient and family history and identification of characteristic findings. A diagnosis may be confirmed by the presence of thread- or rod-like structures (nemaline bodies) on muscle biopsy when stained with Gomori trichrome. A biopsy is the surgical removal and microscopic evaluation of affected tissue. Increasingly the diagnosis is made or confirmed by molecular genetic testing for mutations in the genes known to cause nemaline myopathy.


Neonatal Cholestasis

柠檬酸缺乏所致新生儿肝内胆汁淤积症

Neonatal cholestasis refers to impaired flow of bile at any point from the liver cells into the intestine of a newborn.

The liver is located on the right side of the abdominal cavity just under the rib cage. The liver has many different functions including filtering harmful substances (toxins, including bilirubin) out of the bloodstream, synthesizing proteins, storing essential vitamins, helping to breakdown (metabolize) food to use as energy, creating components that help the blood form clots in response to injury and producing bile, a liquid that plays an essential role in breaking down fats in the small intestine.

Neonatal cholestasis, in general, has many different causes including several viruses including cytomegalovirus and the herpes viruses, various metabolic liver diseases or genetic disorders such as alpha-1-antitrypsin deficiency, PFIC and Alagille syndrome. Other rare disorders may also impair the function of the liver. All of these disorders should be diagnosed promptly. According to the medical literature, 15-20% of cases of neonatal cholestasis run in families (familial form) – and in recent years multiple studies have shown that genetic factors play a role in its development.

The incidence of neonatal cholestasis in the general population is unknown. The proportion of cases classified as idiopathic has diminished as advanced diagnostic techniques and a better molecular understanding of cholestatic diseases in general have allowed physicians to diagnose many infants as being affected with specific syndromes. In the past, these infants would have been included as having idiopathic neonatal hepatitis.

Symptoms of the following disorders can be similar to those of neonatal cholestasis:

Neonatal cholestasis is a diagnosis made by excluding other conditions.


Neonatal Hemochromatosis

Neonatal hemochromatosis is a disorder affecting fetuses and newborns. It is characterized by liver disease associated with the accumulation of excess iron in the liver and other areas of the body. Neonatal hemochromatosis is caused by severe fetal liver disease (see below). Some severe cases result in stillbirth, while live born infants with neonatal hemochromatosis typically show signs within 48 hours of birth. Neonatal hemochromatosis often produces life-threatening complications such as liver failure. However, some infants are less severely affected than others. There is a high risk of recurrence in subsequent pregnancies of women who have had a child with neonatal hemochromatosis. Although the exact cause of the disorder is not fully understood, researchers believe most cases of neonatal hemochromatosis result from maternal fetal alloimmunity, a condition in which antibodies from the mother travel over the placenta and mistakenly attack the fetus.

Neonatal hemochromatosis is characterized by liver disease that is present in the fetus or at birth (congenital). Damage to the liver occurs during pregnancy, ultimately leading to the abnormal accumulation of iron within tissue. Iron accumulation occurs while the fetus is developing in the womb and fetal loss late in pregnancy is common in families with a history of neonatal hemochromatosis. Growth delays within the womb (intrauterine growth deficiencies) are also common and many newborns are born prematurely.

The cause of neonatal hemochromatosis is not fully understood. A woman who has a child with neonatal hemochromatosis has approximately an 80 percent chance of having another child with the disorder. This pattern of recurrence cannot be explained by normal inheritance patterns. Thus, neonatal hemochromatosis appears to be congenital and familial, but not inherited.

Neonatal hemochromatosis is a disorder that affects males and females in equal numbers. The exact incidence of the disorder is unknown. Neonatal hemochromatosis is the most common cause of liver failure in newborns and the most common reason for a liver transplant in newborns. Neonatal hemochromatosis was first reported in the medical literature in 1957.

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

A diagnosis of neonatal hemochromatosis should be suspected in any infants demonstrating liver disease before birth (antenatally) or shortly after birth. Blood tests may reveal elevated levels of ferritin in the blood serum, which may be indicative of liver disease and iron accumulation. Ferritin is an iron compound that is used as an indicator of the body’s iron stores.


Neonatal Lupus

The most common symptom associated with neonatal lupus is a rash that consists of reddish, ring-like skin lesions and resembles the rash associated with systemic lupus erythematosus. The rash is temporary (transient), usually developing during the first few weeks of life and clearing up at some point during the next several months. In rare cases, skin lesions may persist into childhood. The face and scalp are most commonly affected. The raccoon eye patter is a big clue to this diagnosis when it is present.  Less often the rash can occur on the trunk, arms and legs. Some affected infants may also exhibit an abnormal sensitivity to sunlight (photosensitivity), which may initially trigger the development of the rash. Although the most common timing for the rash is about 6 weeks after birth, sometimes the rash may not develop until 2-3 months later. Of note breast feeding is not associated with an increased chance of rash.

Neonatal lupus is a rare acquired disorder that occurs when specific antibodies are passed from a pregnant woman to the developing fetus via the placenta. In most cases, it is the anti-Ro/SSA antibody, the anti-La/SSB antibody, or both. In rare cases, the skin rash associated with neonatal lupus has been associated with another autoantibody that reacts against another type of ribonucleoprotein (the test is called anti-RNP). Other symptoms such as congenital heart block are not thought to occur with anti-RNP but a few isolated cases have been recently published, the importance of which is not yet clear.

Neonatal lupus is a rare condition that has occurred slightly more in female than male infants but is far less female gender dominant than systemic lupus erythematosus. Most symptoms of the disorder, except congenital heart block, are temporary (transient), usually resolving themselves within several months. The exact incidence is unknown, but congenital heart block is estimated to occur in 1 in 15,000 live births.  In general, the heart block associated with maternal autoantibodies occurs in the absence of any structural abnormalities of the heart.

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

There are several syndromes that are characterized by a skin rash that is present at birth (congenital) including Bloom syndrome, Rothmund-Thompson syndrome, Langerhans cell histiocytosis, granuloma annulare, juvenile dermatomyositis, tinea, corporis, erythema multiforme, atopic dermatitis, seborrheic dermatitis, and psoriasis. There are several infections that can occur the weeks just before or after birth (perinatally) including congenital rubella, congenital syphilis, cytomegalovirus, and group B Streptococcus. These disorders usually have additional findings that distinguish them from neonatal lupus. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)


CINCA syndrome

Neonatal-Onset Multisystem Inflammatory Disease

chronic, infantile, neurological, cutaneous and articular syndrome

In addition to fever, symptoms of NOMID involve the skin, CNS and joints. Skin rashes occur in all patients within the first six weeks of life and persist throughout their lives. CNS symptoms include inflammation around the brain (chronic aseptic meningitis), cognitive/mental deficits/learning disabilities, and seizures and sensory organ dysfunction, which can result in vision and hearing loss. Joint inflammation and joint and bone deformities range in severity. Enlargement of the bones around the knee is also characteristic of NOMID.

About 50-60 percent of those who are diagnosed with NOMID have an alteration (mutation) in the CIAS1/NLRP3 gene that codes for the protein cryopyrin (NALP3). Most of the NOMID patients originally described without identifiable mutations were later found to be have somatic mutations a small percentage of their white blood cells (somatic mosaics). Mutations in this gene result in increased activity of a protein complex containing cryopyrin known as the inflammasome, which regulates inflammation in the body. Increased inflammasome activity leads to an increased release of a protein known as interleukin (IL-1ß), which leads to symptoms of inflammation such as fever and joint pain.

NOMID is a very rare disorder; approximately 100 affected individuals with different ethnic backgrounds have been widely reported. Males and females are equally affected.

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

Diagnosis of NOMID is determined through an evaluation of a patient’s symptoms and medical history. Diagnosis includes: skin biopsy, eye exam, hearing test, brain MRI, joint x-rays and cerebrospinal fluid test (detects aseptic meningitis or high white blood counts in the spinal fluid). The diagnosis can be confirmed through genetic testing, but almost half of all NOMID patients do not have an easily identifiable mutation in the CIAS1/NLRP3 gene.


Acquired arginine vasopressin deficiency

The symptoms of NDI can vary from one person to another. Some individuals may be more severely affected than others. The acquired form is almost always less severe than the hereditary forms. In hereditary X-linked NDI, symptoms usually appear shortly after birth and most children are diagnosed within the first year of life. In autosomal dominant NDI, symptoms tend to appear later in life, sometimes not until adulthood. The acquired form of NDI most often occurs in adults and the onset of symptoms may be slow.

A variety of factors can cause acquired NDI. A common cause is chronic use of the drug lithium. Less common causes include protein malnutrition, a variety of kidney diseases, obstruction of the urinary tract and prolonged metabolic imbalances, specifically low levels of potassium in the blood (hypokalemia) or high levels of calcium in the blood (hypercalcemia). Other drugs such as certain antibiotics, antivirals, antifungals or antineoplastic drugs have been reported to potentially cause acquired NDI. During pregnancy, some women may develop a temporary (transient) form of NDI.

The X-linked inherited form of NDI usually affects males. Females can be carriers of the X-linked type, may develop mild symptoms and can pass it on to their male offspring. The autosomal dominant, autosomal recessive and acquired forms of NDI affect males and females in equal numbers. The symptoms of NDI may begin at any age, usually rapidly and without warning. The incidence of NDI is not known; the X-linked form is estimated to affect 4 males out of every 1,000,000.

Symptoms of the following disorders can be like those of NDI. Comparisons may be useful for a differential diagnosis.

A diagnosis of NDI may be suspected based upon the identification of characteristic findings, specifically excessive urination and excessive thirst. A thorough clinical evaluation, a detailed patient and family history, and a variety of specialized tests may be used to confirm a diagnosis. NDI may be suspected in children and adults who present with polyuria and polydipsia. Genetic testing can be done to look for variants in the V2R or AQP2 genes.


Nephrogenic systemic fibrosis

gadolinium-associated nephrogenic systemic fibrosis

Nephrogenic systemic fibrosis (NSF) is a rare disorder that occurs in some individuals with reduced kidney function, who have been exposed to an intravenous contrast material that contains gadolinium. A contrast material is a dye that is sometimes used during magnetic resonance imaging (MRI). The term, fibrosis, refers to the thickening and scarring of connective tissue, most often the consequence of inflammation or injury. NSF is characterized by thickening and hardening (fibrosis) of the skin, subcutaneous tissues, and, sometimes, underlying skeletal muscle. The arms and legs are most often affected. In some cases, the skin on the trunk can also become involved. This proliferation of fibrotic tissue may become systemic, extending to other areas including the smooth, delicate membrane that surrounds the lungs (pleura), the sac surrounding the heart (pericardium), the thin sheet of muscle that aids respiration by moving up and down when breathing (diaphragm), and the outermost layer (dura mater) of the three membranes covering the brain and spinal cord.

The symptoms of NSF may develop slowly over a few weeks to a few months after exposure to gadolinium-based contrast agents. The severity and progression of the disorder can vary from one person to another. The disorder can have a rapid, progressive course and can cause debilitating symptoms. In rare, rapidly-progressive cases, NSF can contribute to the development of severe, life-threatening complications.

The exact underlying cause of NSF is not fully understood. The disorder occurs in individuals with advanced kidney disease who have been exposed to gadolinium-based contrasts agents that are used in magnetic resonance imaging.

NSF was first reported in the medical literature in 2000. The first case was noted in 1997. Researchers believe that the perceived safety and increased availability of gadolinium-based contrast dyes contributed to the rise of NSF since 1997.

Symptoms of the following disorders can be similar to those of NSF.

Diagnostic criteria for NSF have been recently developed. A diagnosis of NSF is usually made based upon a detailed patient history, a thorough clinical examination and identification of characteristic findings. Surgical removal and microscopic study of a small sample of affected skin tissue (skin biopsy) is required to verify the diagnosis. Additional tests may be performed to exclude several other disorders that can resemble NSF.


Neu Laxova Syndrome

Neu-Laxova syndrome (NLS) is a rare genetic disorder that is inherited as an autosomal recessive trait. The syndrome is characterized by severe growth delays before birth (intrauterine growth retardation); low birth weight and length; and distinctive abnormalities of the head and facial (craniofacial) region. These may include marked smallness of the head (microcephaly), sloping of the forehead, widely spaced eyes (ocular hypertelorism), and other malformations, resulting in a distinctive facial appearance. NLS is also typically characterized by abnormal accumulations of fluid in tissues throughout the body (generalized edema); permanent flexion and immobilization of multiple joints (flexion contractures); other limb malformations; and/or abnormalities of the brain, skin, genitals, kidneys, and/or heart.

NLS is associated with distinctive abnormalities before birth. These may include severely delayed growth (intrauterine growth retardation); excessive fluid in the thin-walled membrane (amniotic sac) surrounding the fetus during pregnancy (polyhydramnios); abnormally reduced fetal movements; a short umbilical cord; and an abnormally small placenta. (The placenta is the organ within the uterus that joins the blood supplies of the mother and the developing fetus.) In addition, in some cases, the umbilical cord may have only two blood vessels. (The umbilical cord, which is the flexible structure that connects the fetus with the placenta, normally has two umbilical arteries as well as a larger umbilical vein.)

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

NLS appears to affect males and females in relatively equal numbers. Since the disorder was originally described in three siblings in 1971 (Neu, RL) as well as three siblings in another family in 1972 (Laxova, R), over 30 additional cases have been reported. Investigators suggest that the disorder may have a higher frequency in Pakistanis than in other geographic or ethnic populations.

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

Cerebro-oculo-facio-skeletal (COFS) syndrome is a rare genetic disorder that is sometimes referred to as Pena-Shokeir syndrome type II. Some researchers suggest that NLS and COFS syndrome may represent the same disease entity. (Other investigators have indicated that COFS syndrome and another condition known as Bowen Hutterite syndrome may be the same disorder. [For information on Bowen Hutterite syndrome, please see the description below.]) COFS syndrome is characterized by severe, progressive growth delays after birth (postnatal growth deficiency); characteristic craniofacial malformations, resulting in a distinctive facial appearance; eye (ocular) abnormalities; musculoskeletal defects; and malformations and progressive degenerative changes of the brain and spinal cord (central nervous system). Infants with COFS syndrome fail to gain weight as expected and experience little growth despite an apparently sufficient intake of calories (failure to thrive). Distinctive craniofacial malformations include an unusually small head (microcephaly); a prominent nose and high nasal bridge; an overhanging upper lip; a small mouth, underdeveloped jaw (micrognathia), and receding chin; and large, low-set ears. Most affected infants also have narrow eyelid folds (palpebral fissures), unusually small eyes (microphthalmia), loss of transparency of the lenses of the eyes (cataracts), and/or other ocular abnormalities. Characteristic musculoskeletal defects include permanent flexion of certain fingers (camptodactyly) and particular joints of the arms and legs (flexion contractures); abnormal front-to-back and/or sideways curvature of the spine (kyphosis and/or scoliosis); rocker-bottom feet; characteristic defects of the hips and pelvis; and/or other abnormalities. In addition, central nervous system (CNS) abnormalities are usually present including severe intellectual disability; certain malformations of the brain (e.g., cerebellar hypoplasia, hypoplasia or agenesis of the corpus callosum); and progressive degeneration of myelin (demyelination), a fatty, protective substance around certain nerve fibers that enables the effective transmission of nerve signals. Infants and children with the disorder are also prone to repeated respiratory infections and may experience increasing difficulties breathing (respiratory distress). COFS syndrome is thought to be inherited as an autosomal recessive trait. (For further information, choose Cerebro-oculo-facio-skeletal or COFS as your search term in the Rare Disease Database.)


Neuroacanthocytosis

Neuroacanthocytosis is a general term for a group of rare progressive disorders characterized by the association of misshapen, spiny red blood cells (acanthocytosis) and neurological abnormalities, especially movement disorders. Chorea, which is characterized by rapid, involuntary, purposeless movements, especially of the face, feet and hands, is the most common movement disorder associated with neuroacanthocytosis. Additional symptoms often develop including progressive cognitive impairment, muscle weakness, seizures and behavioral or personality changes. The onset, severity and specific physical findings vary depending upon the specific type of neuroacanthocytosis present. Neuroacanthocytosis syndromes typically progress to cause serious, disabling and sometimes life-threatening complications (and are usually fatal). These disorders are inherited although the mode of transmission can vary. There is disagreement in the medical literature about what disorders should be classified as forms of neuroacanthocytosis. Four distinct disorders are usually classified as the core neuroacanthocytosis syndromes – chorea-acanthocytosis, McLeod syndrome, Huntington’s disease-like 2 and pantothenate kinase-associated neurodegeneration (PKAN). Some medical sources also include abetalipoproteinemia and hypobetalipoproteinemia types I and II as forms of neuroacanthocytosis. This report concentrates only on the four core disorders of neuroacanthocytosis. NORD has a separate report on abetalipoproteinemia.

The symptoms and severity of neuroacanthocytosis can vary from one person to another, even among individuals with the same subtype or among individuals within the same family. It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.

The four core disorders under the umbrella term neuroacanthocytosis are genetic disorders. They are caused by mutations in specific genes. The mode of inheritance and age of onset varies.

Chorea-acanthocytosis most often affects individuals between the ages of 20 and 40, although in rare cases, it can develop in individuals younger than 20 and older than 50. McLeod syndrome typically develops in males between the ages of 40-60. PKAN most often affects children under the age of 10, although in atypical cases onset is often after the age of 20. The age of onset of Huntington’s disease-like 2 is variable. The disorder has been reported only in a few families, all of whom are of African descent. Chorea-acanthocytosis, PKAN and Huntington’s disease-like 2 affect males and females in equal numbers. McLeod syndrome predominantly affects males, although in rare cases females have developed some symptoms of the disorder.

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

A diagnosis of neuroacanthocytosis is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Blood tests can reveal the presence of acanthocytes in the blood, although their absence does not exclude a diagnosis of neuroacanthocytosis. Imaging techniques may aid in obtaining a diagnosis and include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. CT scanning or an MRI may reveal characteristic changes in the brain in individuals with neuroacanthocytosis.


Neurofibromatosis 1

The diagnostic criteria for NF1 were updated by international consensus in 2021. Based on the new criteria, an individual who does not have a parent diagnosed with NF1 will meet clinical diagnostic criteria for NF1 if they demonstrate at least two of the following:

In about 50% of individuals with NF1, the disorder is inherited from a parent. Only one parent need be affected to cause a child to have NF1 (autosomal dominant inheritance). NF1 does not skip generations. Sporadic or random pathogenic variants in the gene responsible for NF1 account for the remaining 50% of cases and occur when a child has NF1 but neither parent does.

NF1 is a rare disorder that affects males and females in equal numbers. NF1 affects all races and ethnic groups equally and is estimated to occur in 1 in 2,500 to 3,000 births.

Symptoms of the following disorders may be similar to those of NF1. Comparisons may be useful for a differential diagnosis:

NF2-related schwannomatosis (NF2) is a rare disorder that is genetically distinct from NF1. NF2 is characterized by noncancerous (benign) tumors on both auditory nerves (vestibular schwannomas) and in other areas of the body. Other tumors of the central nervous system may develop including meningiomas and/or ependymomas. Individuals with NF2 do not typically have cafe-au-lait macules or abnormal skin freckling. Other symptoms of NF2 may include problems with balance, buzzing or ringing in the ears (tinnitus), progressive hearing loss or facial weakness. (For more information on this disorder, choose NF2 as your search term in the Rare Disease Database.)


Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome is a rare but potentially life-threatening reaction to the use of almost any of a group of antipsychotic drugs or major tranquilizers (neuroleptics). These drugs are commonly prescribed for the treatment of schizophrenia and other neurological, mental, or emotional disorders. Several of the more commonly prescribed neuroleptics include thioridazine, haloperidol, chlorpromazine, fluphenazine and perphenazine.

Symptoms of neuroleptic malignant syndrome usually include very high fever (102 to 104 degrees F), irregular pulse, accelerated heartbeat (tachycardia), increased rate of respiration (tachypnea), muscle rigidity, altered mental status, autonomic nervous system dysfunction resulting in high or low blood pressure, profuse perspiration, and excessive sweating.

Neuroleptic malignant syndrome comes about, most likely, as a result of dopamine D2 receptor antagonism. Dopamine is a chemical substance (neurotransmitter) found in the brain and elsewhere in the central nervous system that acts to convey messages from one cell to another. In some way, the use of a particular drug blocks the receptor in the brain cell for dopamine.

Neuroleptic malignant syndrome may affect any person taking neuroleptic drugs. Men appear to be at higher risk than women. Some clinicians believe that the stronger neuroleptic medications are more likely to precipitate an attack of NMS.

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

Anaphylaxis is an abnormally severe allergic reaction to a substance. Major symptoms may include severe itching, hives, flushing, swelling, vomiting, diarrhea, difficulty breathing and unconsciousness. High fever is not a symptom of this disorder. (For more information on this disorder, choose Anaphylaxis as your search term in the Rare Disease Database.)


Neuromyelitis optica spectrum disorder

Neuromyelitis optica spectrum disorder (NMOSD), also known as Devic disease, is a chronic disorder of the brain and spinal cord dominated by inflammation of the optic nerve (optic neuritis) and inflammation of the spinal cord (myelitis). Classically, it was felt to be a monophasic illness, consisting of episodes of inflammation of one or both optic nerves and the spinal cord over a short period of time (days or weeks) but, after the initial episode, no recurrence. It is now recognized that most patients satisfying current criteria for NMOSD experience repeated attacks separated by periods of remission. The interval between attacks may be weeks, months or years. In its early stages, NMOSD may be confused with multiple sclerosis (MS).

The characteristic symptoms of NMOSD are either optic neuritis or myelitis; either may occur as the first symptom. Optic neuritis is inflammation, of the optic nerve (optic neuritis) leading to pain inside the eye which rapidly is followed by loss of clear vision (acuity). Usually, only one eye is affected (unilateral) although both eyes may be involved simultaneously (bilateral). NMOSD may or may not be preceded by a prodromal upper respiratory infection.

Greater than 95% of patients with NMOSD report no relatives with the disease, but approximately 3% report having other relatives with the condition. There is a strong association with a personal or family history of autoimmunity, which are present in 50% of cases. NMOSD is regarded as an autoimmune disease though the exact cause for the autoimmunity is unknown.

NMOSD occurs in individuals of all races. The prevalence of NMOSD is approximately 1-10 per 100,000 individuals and seems to be similar worldwide, although somewhat higher rates have been reported in countries with a higher proportion of individuals of African ancestry. Relative to MS that it mimics, it occurs with greater frequency in individuals of Asian and African descent, but the majority of patients with this illness in Western countries are Caucasian. Individuals of any age may be affected, but typically NMOSD, especially cases seropositive for AQP4-IgG, occur in late middle-aged women. Equal numbers of men and women have the form that does not recur after the initial flurry of attacks, but women, especially those with AQP4-IgG, are four or five times more likely to be affected than men by the recurring (relapsing) form. Children represent may also be affected by this condition; children more commonly develop brain symptoms at onset and seem to have a higher frequency of monophasic presentation than adults.

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

Acute disseminated encephalomyelitis (postinfectious encephalitis) is a central nervous system disorder characterized by inflammation of the brain and spinal cord caused by damage to the fatty sheath surrounding the nerves. This can occur spontaneously, but usually follows a viral infection or inoculation such as a bacterial or viral vaccine. Individuals with acute disseminated encephalomyelitis may have MOG-IgG, adding extra confusion.


Neuropathy, Congenital Hypomyelination

Congenital hypomyelination neuropathy (CHN) is a neurological disorder present at birth. Major symptoms may include respiratory difficulty, muscle weakness and incoordination, poor muscle tone (neonatal hypotonia), absence of reflexes (areflexia), difficulty in walking (ataxia), and/or impaired abilities to feel or move part of the body.

Symptoms of congenital hypomyelination neuropathy and the severity of these symptoms vary from patient to patient.  Major symptoms can include delayed motor (muscle) development (ability to turn over, stand, crawl, walk, etc.), muscle weakness, poor muscle tone (hypotonia), impaired muscle coordination, absence of reflexes (areflexia), difficulty in walking or crawling, and/or impaired ability to feel or move part of the body (mild distal palsy).  In some infants, respiratory problems or difficulty in swallowing may occur. Abnormal microscopic changes in certain nerves such as sural nerves (located in the calf of the leg) can occur.

The exact cause of congenital hypomyelination neuropathy is not known.  The cause of many disorders involving the myelin sheath (the protective sheath surrounding the nerves), such as multiple sclerosis, is unknown.  A recurrent loss and repair of myelin causes congenital hypomyelination neuropathy. Scientists do not yet know why the myelin disappears, nor do they know why it grows back.

Congenital hypomyelination neuropathy is a rare disorder present at birth. It affects males and females in equal numbers.

Symptoms of the following diseases may be similar to those of congenital hypomyelination neuropathy.

Testing for congenital hypomyelination neuropathy includes measuring the velocity of transmission of electrical impulses produced by the muscles (electromyogram), as well as nerve and/or muscle biopsies.


Neurotrophic keratopathy

Neurotrophic keratitis is a rare eye disorder that affects the cornea. The cornea is the clear (transparent) outer layer at the front of the eye. It functions like a window that focuses the entry of light into the eye. The cornea bends light allowing it to pass through the pupil of the eye, eventually reaching the retina, where specialized cells called cones and rods convert light to nerve impulses. These impulses travel along the optic nerve to the brain to become images.

Early on, affected individuals may not have any symptoms of the disorder (asymptomatic). Because the sensitivity of the cornea is reduced, affected individuals often do not complain of pain or discomfort in the eye. Blurred vision, red eyes, dry eyes, and decreased clarity (acuity) of vision can develop. Affected individuals may become extremely sensitive to light (photophobia). The affected cornea can be injured easily, and it heals itself slower than an unaffected cornea does (poor wound healing). This leaves the cornea susceptible to damage. Affected individuals may experience frequent or recurrent corneal erosions, which is when an opening in the epithelial layer develops (epithelial defect). Since the epithelial layer is the protective layer of the cornea, an epithelial defect can leave the eye more susceptible to infection. Patients may or may not be aware of an open epithelial defect because of the reduced or lack of pain in this disease.

Neurotrophic keratitis can be caused by any condition or disorder that affects the nerves that serve the cornea. The main nerve that serves the cornea is called the trigeminal nerve, which is also called the fifth cranial nerve. Damage to the ophthalmic division of the trigeminal nerve, which serves the cornea, can cause neurotrophic keratitis.

Neurotrophic keratitis is a rare disorder. One estimate is that the prevalence is below 5 people per every 10,000 in the general population. Prevalence is the number of people who have a disorder in a specific population at a given time. It is possible that the prevalence is higher because this condition is likely underdiagnosed.

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

A diagnosis of neurotrophic keratitis is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. A diagnosis should be suspected in individuals with unexplained signs of reduced corneal sensitivity and damage to the cornea.


Gorlin syndrome

NBCCS can potentially affect multiple organ systems in the body. However, affected individuals usually will not develop all of the symptoms discussed below. The severity of NBCCS can vary, and some individuals with mild forms can go undiagnosed, while others can have significant complications. Affected individuals and parents of affected children should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.

Nearly all cases of NBCCS have been caused by a variant in the PTCH1 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a variant in a gene occurs, the protein product may be faulty, inefficient or absent. Depending upon the functions of the protein, this can affect many organ systems of the body.

The exact prevalence of NBCCS is unknown. The figure most quoted in the medical literature is 1 individual per 57,000 people in the general population. This figure was based upon a population study in the United Kingdom. However, the authors of that study have revised that figure to approximately 1 in 30,000. The true prevalence of NBCCS in the general population may be higher because mildly affected individuals can go undiagnosed or misdiagnosed. The population prevalence of damaging genetic mutations in PTCH1 (https://gnomad.broadinstitute.org/gene/ENSG00000185920?dataset=gnomad_r4) would predict a disease prevalence that may be as high as 1/12,000.

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

A diagnosis of NBCCS is based on identification of a disease-causing variant in   PTCH1, PTCH2 or SUFU. Genetic testing is almost always positive in typical cases of NBCCS. However, there are rare gene variants that are missed by standard laboratory procedures.


Epidermal nevus syndrome

The specific symptoms and severity of nevus sebaceus syndrome can vary greatly from one person to another. It is important to note that affected individuals may not have all the symptoms discussed below. Affected individuals or their parents should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.

Individuals with nevus sebaceus syndrome have variants of the KRAS and HRAS genes that are not inherited but occur after fertilization of the embryo (postzygotic). HRAS and KRAS variants have also been found in people with isolated sebaceous nevi who do not have abnormalities in other organs. These gene variants are only found in the nevi and are not present in the surrounding skin.

Nevus sebaceus syndrome affects males and females in equal numbers. The exact prevalence and incidence of the disorder in the general population are unknown. Epidermal nevi—as an isolated finding or a part of a syndrome—have been reported to occur in approximately 1 to 3 per 1,000 live births.

Keratinocytic epidermal nevus (KEN) syndrome is a form of epidermal nevus syndrome involving a keratinocytic epidermal nevus. The lesions of this disorder are characterized by epidermal hyperplasia, without the enlarged and malformed sebaceous glands seen in sebaceus nevi. The associated abnormalities in other organs are similar to those seen in nevus sebaceus syndrome. The exact same postzygotic variants of the KRAS and HRAS genes have been identified in KEN. KEN has also been associated with variants in the FGF3 gene and keratins 1 and 10 (causing epidermolytic KEN).

A diagnosis of nevus sebaceus syndrome is made based upon identification of characteristic symptoms (e.g., a sebaceous nevus, along with abnormalities affecting other organ systems). A detailed patient history and a thorough clinical evaluation are crucial to the diagnosis and management of this disorder.


NF2-Related Schwannomatosis

Bilateral acoustic neurofibromatosis (BANF)

NF2-related schwannomatosis (NF2; previously known as neurofibromatosis 2) is a rare genetic disorder that is primarily characterized by noncancerous (benign) tumors of the nerves that transmit balance and sound impulses from the inner ears to the brain (bilateral acoustic neuromas/vestibular schwannomas). Symptoms may become apparent during childhood, adolescence, early adulthood or later in adult life. Depending on the exact location and size of the acoustic neuromas/vestibular schwannomas, or other schwannomas such findings may include problems with balance and walking (gait); dizziness; headache; facial weakness, numbness, or pain; but more typically ringing in the ears (tinnitus); and/or progressive hearing loss.

The characteristic symptoms of NF2 usually develop around the time of puberty or during early adulthood. These symptoms may include problems with balance, buzzing or ringing in the ears (tinnitus) and/or gradual hearing loss. These symptoms usually result from the presence of benign tumors on both vestibular nerves pressing on the adjacent auditory nerves (acoustic neuromas vestibular schwannomas). Almost all affected individuals develop bilateral vestibular schwannomas by age 30 years. Other tumors of the central nervous system may also develop, and can include hybrid tumors, meningiomas, low grade ependymomas of the spinal cord), and non-vestibular schwannomas on the other cranial nerves, spinal nerves or peripheral nerves. The size, location, and number of tumors may vary in different people affected. (For more information on tinnitus, choose tinnitus as your search term in the Rare Disease Database.)

NF2 is caused by a variant in the NF2 gene. The NF2 gene regulates (encodes for) the production of a protein known as merlin/schwannomin that plays a role in suppressing the development of certain tumors (tumor suppressor). According to investigators, merlin/schwannomin is related to a class of proteins (ezrin-radixin-moesin proteins) that serve to link the internal, supportive system within a cell (cytoskeleton) to proteins in cell membranes. Several different types of variants of the NF2 gene have been identified in individuals with the disorder (e.g., large deletions, nonsense, splice site, missense and frameshift variants). Investigators suggest that different variants in the gene may contribute to the wide variability of symptoms and findings in affected individuals.

NF2 is a rare disorder that affects males and females in equal numbers. All races and ethnic groups are equally affected by this disorder. The estimated incidence of NF2 is 1 in 33,000 people worldwide. The symptoms of this disease typically become apparent during puberty or early adulthood. The average age of onset is 18 to 24 years.

Symptoms of the following disorders can be similar to those of neurofibromatosis 2. Comparisons may be useful for a differential diagnosis:

The treatment of vestibular (acoustic) neuromas associated with NF2 is the surgical removal of the tumors, when possible. The surgical procedure that is performed is based upon the size and precise location of the tumors. Radiation therapy may be considered for some individuals with this disorder, especially those who are not candidates for surgery. The VEGF inhibitor bevacizumab may also be considered to treat rapidly growing schwannomas.


无泪-舞蹈手足徐动症-肝功能障碍综合征

NGLY1-related congenital disorder of deglycosylation

NGLY1 deficiency is a rare disorder that can affect multiple systems of the body. Affected individuals may have delays in reaching developmental milestones, intellectual disability, movement disorders, seizures, liver disease, and an inability to produce tears when they cry (alacrima), or they may produce tears very infrequently. The specific symptoms and severity of this disorder can vary dramatically among affected individuals. Additional symptoms can develop in some children. NGLY1 deficiency is caused by a disease causing (pathogenic) variant (mutation) in the NGLY1 gene. This variant is inherited in an autosomal recessive pattern. As of April of 2021, fewer than 100 individuals with NGLY1 deficiency have been identified. It is possible that only the most severely affected children have been diagnosed and that descriptions of this disorder reflect these severely affected individuals. This happens because more severely affected children are more likely to be referred to specialists, receive genetic testing, and receive a diagnosis. Some researchers believe that affected individuals with milder forms of NGLY1 deficiency most likely exist.

Although researchers have been able to establish a clear syndrome with characteristic or core symptoms, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing a complete picture of associated symptoms and prognosis. As researchers learn more about the disorder, the potential spectrum or specific pattern of symptoms will be clearer. Therefore, it is important to note that every child is unique and that an individual child may not have all the symptoms discussed below.

NGLY1 deficiency is caused by disease causing (pathogenic) variants in the NGLY1 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.

NGLY1 deficiency is an extremely rare disorder that was first reported in the medical literature in 2012. According to the NGLY1 Foundation, as of April 2021, there are approximately 75 individuals worldwide who have been identified with the disorder. Rare diseases like NGLY1 deficiency often go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population.

Symptoms of the following disorders can be similar to those of NGLY1 deficiency. Comparisons may be useful for a differential diagnosis.

A diagnosis of NGLY1 deficiency is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. There are no formal diagnostic criteria established for this disorder. A combination of characteristic symptoms including developmental delays, alacrima, hyperkinetic movement disorders, and liver disease may prompt testing for the disorder.


Niemann Pick Disease Type C

Individuals with NPC can have onset of symptoms at different ages that have been grouped historically as: perinatal (shortly before and after birth), early infantile (3 months to < 2 years), late infantile (2 to < 6 years), juvenile (6 to < 15 years), and adult (15 years and greater).  NPC affects neurologic and psychiatric functions, as well as various internal organs (visceral).  Symptoms arise at different times and follow independent progression.  Visceral symptoms are more typically seen in individuals presenting at a younger age.  Neurologic and psychiatric symptoms often occur slowly over time, and thus feature more prominently in individuals presenting in the later age groups.

Individuals with NPC have mutations in one of two genes, NPC1 or NPC2. Approximately 95% of affected individuals have mutations in NPC1. Genes provide instructions for producing proteins that play a critical role in many functions of the body. Mutations in a gene may lead to the production of a protein that has reduced or abnormal functions, or to the absence of the protein. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.

NPC affects males and females in equal numbers, and can affect individuals of any ethnic background (pan ethnic). NPC is estimated to occur in 1 in 100,000-120,000 live births. However, many cases go misdiagnosed or undiagnosed, making it difficult to determine the disorder’s true frequency in the general population.

Symptoms of the following disorders can be similar to those of NPC. Comparisons may be useful in considering other potential diagnoses.

Niemann-Pick disease type C is diagnosed based on characteristic symptoms obtained from a thorough clinical evaluation (see under Signs and Symptoms), and confirmed by a variety of specialized tests. Proper diagnosis of NPC requires physicians to suspect the diagnosis based upon symptoms, and to follow up with appropriate laboratory tests to evaluate the function of the protein or the presence of accumulated byproducts (biochemical tests), and to identify mutations in the NPC1 or NPC2 gene (gene sequencing).


Nocardiosis

Nocardiosis is an infectious pulmonary disease characterized by abscesses in the lungs. These abscesses may extend through the chest wall. The infection is spread through the body via the bloodstream by a microorganism called Nocardia asteroides.

Most cases of nocardiosis begin as pulmonary infections that develop into lung abscesses.  Symptoms may include chest pain, cough, bloody sputum, sweats, chills, weakness, lack of appetite, weight loss and difficult or labored breathing.  Nocardiosis symptoms are similar to those of pneumonia and tuberculosis.

Nocardiosis is caused by Nocardia asteroides, a bacterium that is carried up into the air from the ground and may be inhaled.  Other species of the same family of bacteria such as Nocardia brasiliensis, Nocardia caviae, and Nocardia farcinica, are also known to cause disease. The organism usually enters the body through the lungs or, more rarely, through the gastrointestinal tract or the skin.

Nocardiosis occurs worldwide.  Those affected tend to be older adults, and males are more often affected than are females.

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

Actinomycosis is a chronic infectious disease characterized by draining sinuses.  The microorganisms which cause Acitnomycosis are often found on the gums, tonsils and teeth.  Actinomycosis most commonly affects adult males. The most common entry into the body for the infecting microorganism is through decayed teeth.  Pulmonary or abdominal disease may also occur due to this infection.  The infection causes  small abscesses which spread to adjoining tissue.  The abdominal form of the infection produces symptoms of pain, fever, vomiting, diarrhea or constipation and emaciation.   There may be an abdominal mass with signs of intestinal obstruction, and draining pus may develop in the abdominal wall.  In the thoracic form of the infection, lung infection may resemble tuberculosis with chest pain, fever and a cough with sputum.