Non-24-Hour Sleep-Wake Disorder

非24小时睡眠-觉醒综合征

circadian rhythm sleep disorder, free-running type

Non-24-hour sleep-wake disorder (N24) is a circadian rhythm sleep disorder in which an individual’s biological clock fails to synchronize to a 24-hour day. Instead of sleeping at roughly the same time every day, someone with N24 will typically find their sleep time gradually delaying by minutes to hours every day. They will sleep at later and later clock times until their sleep periods go all the way around the clock. (In extremely rare cases the sleep rhythm will gradually advance rather than delay.) Patients’ cycles of body temperature and hormone rhythms also follow a non-24-hour rhythm. Attempts to fight against this internal rhythm and sleep on a typical schedule result in severe and cumulative sleep deprivation. N24 occurs in 55-70% of completely blind people, but also occurs in an unknown number of sighted people.

As most people are required to keep a regular schedule for work, school, or other social obligations, the first symptoms of N24 usually noticed are periodic night-time insomnia and excessive daytime sleepiness. Due to the cyclical nature of the disorder, some affected persons will tend to feel normal for periods of days to weeks when their body’s rhythm is synchronized with the rhythm of society around them. As the individual’s body once again desynchronizes from the rhythms of the light-dark cycle (or day-night cycle) and the obligations the individual with N24 is trying to maintain, the insomnia and excessive daytime sleepiness will return.

All life on earth has evolved in conditions of a 24-hour day-night (light-dark) cycle. Organisms have evolved mechanisms to time their cellular and metabolic processes to anticipate this daily rhythm. As a result, within nearly all cells of the human body there is a biological clock based on a cycle of DNA and protein synthesis. Clock gene activity has been found within white blood cells and cells of the heart, brain, liver and many other tissues.

While the total number of people living with N24 is unknown, researchers assume that more blind people are affected than sighted people. It is estimated that 55-70% of all people who are totally blind have N24. People who lack any light perception (for example those whose eyes are enucleated) are more likely to be affected than those with some retinal function. The frequency of N24 among the sighted is unknown but the world-wide medical literature provides case studies of roughly 100 sighted individuals with N24. Fifty-seven of these cases appear in a single Japanese study. The Circadian Sleep Disorders Network (see under organizations) has 98 members who have indicated they or a family member have N24. The Facebook N24 group has over 500 members but it is not known how many are actual patients. As the condition is not widely known, there may be a significant number of undiagnosed cases.

Symptoms of the following disorders can be similar to those of N24. Comparisons may be useful for differential diagnosis.

Initial diagnosis is based on home sleep logs kept by the patient that show a non-24-hour sleep pattern. This is usually more easily distinguished if the patient’s sleep times are not constrained by social or occupational obligations.


Glycine encephalopathy

Non-ketotic hyperglycinemia (NKH) is a rare, genetic, metabolic disorder caused by a defect in the enzyme system that breaks down the amino acid glycine, resulting in an accumulation of glycine in the body’s tissues and fluids. There is a classical form of NKH and a variant form of NKH. The classical form is then further divided into severe disorder or an attenuated form (mild form).

The severe classic form of NKH typically presents in the first week of life with low muscle tone, lethargy, seizures, coma, and apnea requiring ventilator support. The ventilator is typically needed for a period of 10-20 days before the apnea resolves. A portion of individuals with severe classical NKH die during the neonatal period, often due to withdrawal of intensive care supports.  All children with severe classical NKH who survive the neonatal period have severe developmental delay. Most individuals do not reach milestones past those reached by the typical 6-week-old infant. Seizures gradually worsen and can be difficult to control. Feeding difficulties and orthopedic problems can occur. Airway maintenance becomes poor over time due to low muscle tone, and is often the cause of death.

Classic NKH is caused by genetic variants (mutations) in the genes that encode the components of the glycine cleavage enzyme system. This enzyme system is responsible for breaking down the amino acid glycine in the body. When it is not working properly, glycine accumulates in the body, resulting in the symptoms associated with NKH.

The incidence of NKH is predicted to be approximately 1:76,000. NKH can occur in individuals of any ancestry.

Symptoms of the following disorders can be similar to those of non-ketotic hyperglycinemia. Comparisons may be useful for a differential diagnosis:

Ketotic hyperglycinemia: propionic acidemia, methlymalonic acidemia, isovalerica acidema and B-ketothiolase deficiency. These patients have elevated glycine due to interference with the glycine cleavage enzyme system, but do not resemble NKH clinically.


Pulmonary non-tuberculous mycobacterial infection

Nontuberculous Mycobacterial Lung Disease

Mycobacteria other than tuberculosis (MOTT)

Nontuberculous mycobacterial (NTM) lung disease is a general term for a group of disorders characterized by exposure to specific bacterial germs known as mycobacteria. These germs are found in the water and soil and are common throughout the environment as a whole. They usually do not cause illness. The term ‘nontuberculous’ is used to differentiate these disorders from the mycobacterium that cause tuberculosis (i.e. mycobacterium tuberculosis complex). These disorders also exclude Mycobacterium leprae, the mycobacterium that causes leprosy. In NTM disorders, the severity of infection and the disease course can vary greatly from one person to another. The most common symptoms include a persistent cough, fatigue, weight loss, night sweats, and occasionally shortness of breath (dyspnea) and coughing up of blood (hemoptysis). Less often, NTM infection can cause skin or soft tissue infections or infection and inflammation of the lymph nodes (lymphadenitis). Most evidence indicates that these infections are not transmitted from one person to another, but are acquired from the environment. NTM lung disease most commonly affects people with an underlying lung disease such as chronic obstructive pulmonary disease (COPD), bronchiectasis, cystic fibrosis, primary ciliary dyskinesia, and alpha-1-antitrypsin disease, but individuals with no prior history of lung disease can also be affected. Less severe infections may not require treatment. In other cases, the infection can become chronic requiring ongoing treatment.

The symptoms and severity can vary greatly from one person to another. The reason for this variability is not fully understood. Chronic lung infection is the most common complication affecting approximately 94% of individuals. The symptoms are usually nonspecific and similar to the symptoms seen in other lung or respiratory infections. Such symptoms include cough, fatigue, shortness of breath (dyspnea), coughing up of blood (hemoptysis), excessive mucus (sputum) production, fever, night sweats, loss of appetite, and unintended weight loss. Wheezing and chest pain may also occur. Affected individuals may experience recurrent respiratory infections. In some cases, these infections can cause progressive damage to the lungs and, eventually, the lungs will not function as well as they should (impaired lung function).

Nontuberculous mycobacterial lung disease is caused by infection with specific bacterial germs known as mycobacteria. These germs are commonly found throughout the environment. Most people do not become sick when exposed to these germs. More than 120 species of mycobacteria have been identified that can cause disease in humans. The most common are Mycobacterium avium complex or MAC. MAC encompasses three mycobacterial species known as M. avium,M. intracellulare, and M. chimaera. Collectively, these species account for approximately half of all mycobacterial infections.

In North America, the incidence of nontuberculous mycobacterial lung disease is rising, particularly among the elderly. Generally, NTM infection is more common in Caucasians, Asians and individuals with a compromised immune system. The incidence and prevalence rates reported in the medical literature varies and because many cases may go undiagnosed or misdiagnosed determining the true frequency of NTM infections in the general population is difficult.

Symptoms of the following disorders can be similar to those of nontuberculous mycobacterial lung disease. Comparisons may be useful for a differential diagnosis.

A diagnosis of nontuberculous mycobacterial lung disease is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. However, the diagnosis can be challenging because the characteristic signs and symptoms are highly variable and nonspecific. A diagnosis of NTM includes ruling out other diseases such as tuberculosis or lung cancer.


努南综合征伴多发雀斑样痣

Noonan syndrome with multiple lentigines

Noonan Syndrome with Multiple Lentigines

The symptoms and physical characteristics associated with NSML are highly variable. However, most affected individuals tend to exhibit characteristic abnormalities of the skin, the structure and function of the heart, the head and facial (craniofacial) area, and/or the genitals.

NSML is an autosomal dominant genetic disorder caused by an abnormality (change) in one of two genes: PTPN11 or RAF1. Mutations in these genes also cause a different genetic condition called Noonan syndrome. Approximately 90% of individuals with NSML have a mutation in the PTPN11 gene and most individuals who do not have a PTPN11 gene mutation have a RAF1 gene mutation. A single patient with a mutation in the BRAF gene, belonging to the same molecular pathway as PTPN11 and RAF1, has been described.

NSML is an extremely rare disorder that is believed to affect males and females in equal numbers.

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

Noonan syndrome and NSML are both caused by mutations in the PTPN11 and RAF1 genes. The characteristics seen in both of these conditions include hypertelorism, broad chest, short stature, developmental delay, pulmonic stenosis, hypertrophic cardiomyopathy, and a chest abnormality. Noonan syndrome is an autosomal dominant genetic disorder characterized by a distinctive facial appearance, webbing of the neck (pterygium colli), short stature, chest abnormalities, congenital heart defects, and/or other abnormalities. Characteristic malformations of the head and facial (craniofacial) area may include widely-set eyes (ocular hypertelorism); downwardly slanting eyelid folds (palpebral fissures); drooping of the upper eyelids (ptosis) or unusually thick, hooded eyelids; a prominent upper lip; and/or low-set, prominent external ears (pinnae) that are abnormally rotated toward the back of the head (posteriorly angulated). Most affected individuals also have a distinctive chest malformation characterized by abnormal protrusion of the upper (superior) portion of the breastbone (sternum) and/or abnormal depression of the lower (inferior) portion of the breastbone (pectus carinatum and/or pectus excavatum, respectively). In many males with Noonan syndrome, one or both testes may have failed to descend into the scrotum (unilateral or bilateral cryptorchidism). In addition, affected individuals often have congenital heart defects, particularly obstruction of the normal flow of blood from the lower right chamber (ventricle) of the heart to the lungs (valvar pulmonary stenosis).


Noonan Syndrome

Noonan syndrome is a genetic disorder that is typically evident at birth (congenital). The disorder is characterized by a wide spectrum of symptoms and physical features that vary greatly in range and severity. In many affected individuals, associated abnormalities include a distinctive facial appearance; a broad or webbed neck; a low posterior hairline; a typical chest deformity and short stature. Characteristic features of the head and facial (craniofacial) area may include widely set eyes (ocular hypertelorism); skin folds that may cover the eyes’ inner corners (epicanthal folds); drooping of the upper eyelids (ptosis); a small jaw (micrognathia); a depressed nasal root; a short nose with broad base; and low-set, posteriorly rotated ears (pinnae). Distinctive skeletal malformations are also typically present, such as abnormalities of the breastbone (sternum), curvature of the spine (kyphosis and/or scoliosis), and outward deviation of the elbows (cubitus valgus). Many infants with Noonan syndrome also have heart (cardiac) defects, such as obstruction of proper blood flow from the lower right chamber of the heart to the lungs (pulmonary valvular stenosis) and thickening of the ventricular heart muscle (hypertrophic cardiomyopathy). Additional abnormalities may include malformations of certain blood and lymph vessels, blood clotting and platelet deficiencies, learning difficulties or mild intellectual disability, failure of the testes to descend into the scrotum (cryptorchidism) by the first year of life in affected males, and/or other symptoms and findings.

Individuals with Noonan syndrome have associated symptoms and physical findings that vary greatly in range and severity from person to person. Some affected individuals have only minor facial abnormalities; others may have the majority of symptoms and findings associated with the disorder, such as distinctive features of the head and facial (craniofacial) area, a broad or webbed neck, short stature, skeletal malformations, congenital heart defects, malformations of certain blood and lymph vessels, blood clotting and platelet deficiencies, attention issues, mild intellectual disability, and/or other abnormalities.

Noonan syndrome is most often an autosomal dominant genetic disorder caused by abnormalities (mutations) in several different genes, the main ones being: PTPN11, KRAS, SOS1 RIT1 and RAF1. PTPN11 mutations have been found in approximately 50% of affected individuals; KRAS mutations have been found in fewer than 5% of those affected; SOS1 mutations have been seen in approximately 13% of people with Noonan syndrome; RIT1 mutations have been seen in approximately 5% of people with Noonan syndrome, and RAF1 mutations are observed in 5% of those affected. Additional genes associated with Noonan syndrome have been identified in fewer cases: NRAS, BRAF, MEK2, RRAS, RASA2, A2ML1, and SOS2. Two conditions with overlap are newly described in association with mutations in SHOC2 and CBL.  Noonan syndrome caused by pathogenic variants in LZTR1 can be inherited in either an autosomal dominant or an autosomal recessive manner.

Noonan syndrome appears to affect more males than females and is thought to affect approximately one in 1,000 to one in 2,500 people. However, other reports indicate that the disorder may affect more than one in 1,000 newborns in the general population. Since Noonan syndrome was originally reported in 1883 (O. Kobylinski) and more thoroughly described in 1963 (J.A. Noonan and D.A. Ehmke), more than 500 patients shave been discussed in the medical literature. Because Noonan syndrome is extremely variable and therefore may be under- or misdiagnosed, it may be difficult to determine the true frequency of the disorder in the general population.

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

Cardiofaciocutaneous (CFC) syndrome, an extremely rare genetic disorder, is characterized by a distinctive facial appearance similar to that seen in children with Noonan syndrome. Additional primary characteristics may include unusually sparse, brittle, curly hair; skin abnormalities; heart malformations that are present at birth (congenital heart defects); growth delays; and moderate to severe intellectual disability. Individuals with cardiofaciocutaneous syndrome typically have an unusually large head (macrocephaly), a prominent forehead, and abnormal narrowing of both sides of the forehead (bitemporal constriction); a short, upturned nose with a depressed nasal root; eye findings including downwardly slanting eyelids (palpebral fissures), widely spaced eyes (ocular hypertelorism), and/or drooping of the upper eyelids (ptosis). In most patients, congenital heart defects are also present, particularly obstruction of the normal flow of blood from the lower right chamber (ventricle) of the heart to the lungs (pulmonary valve stenosis) and/or an abnormal opening in the fibrous partition (septum) that divides the two upper chambers (atria) of the heart (atrial septal defects). Thickening of the heart muscle (hypertrophic cardiomyopathy) can also be found. In addition, most individuals with the disorder experience growth delays, moderate to severe intellectual disability, and abnormal delays in the acquisition of skills requiring the coordination of mental and muscular activity (psychomotor retardation). Cardiofaciocutaneous syndrome is caused by mutations in several genes: BRAF, MEK1 and 2, and KRAS. (For more information choose CFC Syndrome as your search term in the Rare Disease Database.)


Norrie disease

The main symptom of Norrie disease is a retinal degeneration which occurs before birth and results in blindness at birth (congenital) or early infancy, usually by 3 months of age. Visual failure in this disorder is characterized by the abnormal development of the neuroretina, the thin layer of nerve cells that lines the back of the eyes. The neuroretina senses light and converts it into nerve signals, which are then relayed to brain through the optic nerve.

Norrie disease occurs due to a mutation of the NDP gene located on the X chromosome. The NDP gene encodes a protein known as norrin which plays a role in cell and tissue development. It is believed to be essential for the proper development of blood vessels (angiogenesis), especially those that supply blood to the retina and the cochlea of the inner ear. Norrin is an essential ligand for the frizzled-4 receptor of the Wnt cascade pathway, which contributes to cell development and specialization. Mutations in the NDP gene can prevent the protein from working correctly.

The incidence and prevalence rates for Norrie disease are unknown. The disorder has been reported in all ethnic groups.

Symptoms of the following disorders can be similar to those of Norrie disease. Comparisons may be useful for a differential diagnosis. Common differential diagnoses include retinoblastoma with unilateral pseudoglioma, retinopathy as a result of prematurity, persistent hyperplastic primary vitreous and familial exudative vitreoretinopathy.

A diagnosis of Norrie disease is suspected based upon a detailed patient history, a thorough clinical evaluation, and identification of characteristic findings. There may be a family history supporting X-linked inheritance. There are no biochemical or functional assays available for diagnosis. A diagnosis may be confirmed by molecular genetic testing in which a mutation in the NDP gene is identified.


NORSE (New Onset Refractory Status Epilepticus) and FIRES (Febrile Infection-Related Epilepsy Syndrome)

In two-thirds of NORSE cases, the course of the syndrome begins with a mild febrile illness, associated with malaise, fatigue and symptoms of upper respiratory tract or gastro-intestinal tract infection. Symptoms of meningeal inflammation, such as headache and photophobia, are uncommon. Behavioral and cognitive symptoms, such as apathy or agitation, amnesia, and sometimes hallucinations can be observed. The presence of hallucinations may suggest an autoimmune etiology, especially anti-NMDA receptor encephalitis.

The most common causes of NORSE and FIRES are autoimmune/paraneoplastic disorders, such as encephalitis associated with anti-neuronal antibodies (anti-NMDA receptor, anti-voltage-gated potassium channel complex, etc.), followed by viral encephalitis. Genetic epilepsy syndromes associated with sensitivity to fever do not represent a major cause of NORSE and FIRES, as suggested by one study in children that did not find mutations in the SCN1A (the gene mostly associated with Dravet syndrome), PCDH19 or POLG1 (Alpers syndrome) genes. However, studies found genetic polymorphisms in the SCN2A gene (another gene involved in Dravet syndrome) and in the IL1RN gene (a gene coding for an immunomodulatory protein) in children with FIRES. These data are still very limited and further studies are required to fully explore the hypothesis of a genetic predisposition.

NORSE and FIRES can occur at any age but preferentially affect young adults and school-age children, with a second peak occurring around age 65. In adults, females are more likely to be affected than males, but probably not in children. The idiopathic hemiconvulsion-hemiplegia and epilepsy syndrome (IHHE) is a related syndrome seen only in infants as discussed above.

Several epilepsy syndromes in infants and children share many similarities with NORSE and FIRES, and many are likely different terms for the same condition. All these syndromes have in common an acute onset, a prolonged course of refractory SE, and inflammatory features in the CSF. These related disorders include:

The diagnosis of NORSE or FIRES, as a clinical presentation, is usually made on clinical grounds in patients who develop refractory SE once obvious causes of SE have been excluded. The diagnosis of cryptogenic NORSE or FIRES can only be made once uncommon causes of SE have been carefully excluded (see Clinical Testing and Work-Up section below), which typically takes several weeks to complete.


Obstructive Hypertrophic Cardiomyopathy

idiopathic hypertrophic subaortic stenosis

The type and severity of symptoms of oHCM may be very different from person to person, even within the same family. Many people with oHCM have few or no symptoms. The first symptoms of oHCM can appear at any age, but most often start in early adulthood. Symptoms are often mild but may get worse over time. Sometimes symptoms get worse very quickly, while in others, symptoms progress slowly or not at all. The age at which symptoms start to get worse can also vary from person to person.

Based on current knowledge, oHCM can be caused by changes (pathogenic variants) in 11 different genes. Variants in any one of these genes disrupt the formation of the cells of the heart wall, impacting the way the heart muscle contracts. This leads to thickening of the wall between the two ventricles, eventually blocking blood flow out of the heart. About 80% of people with HCM have a disease-causing variant in the MYBPC3 or MYH7 gene.

Hypertrophic cardiomyopathy (HCM) affects between 1/200 to 1/500 people. It has been diagnosed equally in males and females and in all ethnic and racial groups. It has been estimated that there are at least 750,000 people in the United States with HCM and about 15-20 million people with HCM worldwide. Because people with HCM often do not have obvious symptoms, it is thought that only 10% of people with HCM get diagnosed. In a large study using a national database of private insurance claims, the authors found that the prevalence of oHCM was 1.65 per 10,000 individuals in 2016 and remained fairly stable over the 3-year time period.

Other types of cardiomyopathies include the following:

oHCM is diagnosed based on the symptoms, clinical examination, a detailed family history, laboratory testing and imaging of the heart. Because the symptoms of hypertrophic cardiomyopathy look the same as the symptoms of other more common conditions such as high blood pressure, anxiety or asthma, these more common conditions need to be excluded before a diagnosis of hypertrophic cardiomyopathy can be made. The most useful tests for diagnosing oHCM are a special ultrasound of the heart known as an echocardiogram and a special type of MRI called cardiac magnetic resonance (CMR). Both echocardiogram and CMR look at the heart structure and function.

There is currently no cure for oHCM. The treatment is based on managing the symptoms. For mild symptoms, initial treatment may include medications that slow down and reduce the force of heart contractions. Other medications can be used to reduce blood pressure and regulate the heartbeat. However, these medications have not been adequately proven in clinical trials designed specifically for oHCM patients. Lifestyle and diet changes may also be part of the treatment. Avoiding intense isometric exertion, dehydration and excessive alcohol intake is recommended. Based on current knowledge, aerobic exercise is not restricted, but in fact recommended. Maintaining an ideal body weight is helpful. Many patients also have sleep apnea and testing for and treating that condition is important.


眼白化病伴发迟发性感觉神经性聋

Ocular Albinism with Late Onset Sensorineural Deafness

Ocular albinism with late onset sensorineural deafness (OASD) is a rare inherited subtype of ocular albinism.

The main symptoms include ocular albinism and deafness. Albinism refers to lack of melanin synthesis, or the pigment of skin, eyes and hair.

There is no consensus regarding the true cause of OASD, but it is likely closely tied to the cause of ocular albinism type 1 (OA1).

It is estimated that fewer than 1,000 people in the U.S. have OASD. Since the disorder follows an X-linked recessive inheritance pattern, more males are affected than females.

OASD belongs to a group of interconnected syndromes associated with OA1. These syndromes result from the deletion or duplication of a set of genes located close together. Many people with contiguous gene syndromes, characterized by gene variants in the Xp22.3 region, have been reported to have albinism.

Diagnosis is often suspected early in life based on lack of color (hypopigmentation) of the eyes, vision abnormalities and family history. Diagnostic testing typically involves working with a geneticist and doing adequate molecular testing to identify the variants in the GPR143 gene that are known to be associated with OASD. Molecular genetic tests can be used to analyze entire gene coding sequences and areas of gene deletion or duplication. Family history information can be useful to look for an X-linked inheritance pattern.

There are no definitive treatments for OASD, but several actions can be taken to lessen symptoms.


Ocular Albinism

Ocular albinism type I (OA1), or X-linked ocular albinism, is the most common form of ocular albinism. Ocular albinism is a genetic disorder characterized by vision abnormalities in affected males. Vision deficits are present at birth and do not become more severe over time. Affected individuals have normal skin and hair pigmentation. Ocular albinism is inherited as an X-linked recessive genetic condition and caused by mutations in the G protein-coupled receptor 143 (GPR143) gene.

Ocular albinism primarily affects pigment production in the eyes. Several vision problems can occur with ocular albinism including an involuntary movement of eyes back and forth (nystagmus), reduced iris pigment in some individuals, reduced retinal pigment, lack of development of the fovea (foveal hypoplasia) leading to blurred vision, and abnormal connections in the nerves from the retina to the brain that prevents the eyes from tracking together and reduces depth perception. Crossed eyes (strabismus) and sensitivity to light (photophobia) are also common. Typically individuals have normal hair and skin pigmentation.

Mutations in the G protein-coupled receptor 143 (GPR143) gene on the X chromosome encoding a protein of 404 amino acids and are associated with ocular albinism type I (OA1). This protein is expressed in the retinal pigment epithelium (RPE) of the eye and melanocytes. GPR143 interacts with the premelanosomal protein MART1 which also plays a role in the regulation of melanin pigment formation. MART1 may act as a chaperone protein for GPR143. Mutations in GPR143 result in enlarged aberrant premelanosomes with aberrant fibril formation. There is also a decrease in melanin pigment synthesis in the premelanosome. The premelanosome is the intracellular location of melanin pigment production in the pigment cell. Aberrations of melanosomes in the skin are also present, but do not seem to reduce the amount of skin and hair pigment. GPR143 is also thought to be a receptor for L-DOPA (L-3,4-dihydroxyphenylalanine), an intermediate metabolite in the melanin pigment pathway, and may be involved in intracellular signaling in the retina.

The prevalence of ocular albinism has been reported to be one male in 20,000 births.

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

Oculocutaneous albinism is a group of rare inherited disorders characterized by a reduced amount or complete lack of color (pigmentation) in the skin, hair, and eyes. These conditions are caused by mutations in specific genes that are necessary for the production of melanin pigment. Abnormal or insufficient melanin pigment results in vision abnormalities and light skin that is very susceptible to damage from the sun. In some cases, individuals with oculocutaneous albinism can have near normal skin and hair pigmentation as seen in ocular albinism, making it appear to be X-linked ocular albinism, but these individuals are usually born with reduced skin and hair pigmentation and accumulate pigment with time unlike individuals with ocular albinism who are born with normal skin and hair pigmentation. Oculocutaneous albinism is inherited as an autosomal recessive genetic condition. (For more information on this disorder, choose oculocutaneous albinism as your search term in the Rare Disease Database.)


Ocular motor apraxia, Cogan type

眼运动失用症Cogan型

Cogan type ocular motor apraxia is a rare congenital disorder characterized by a defect in side-to-side (horizontal) eye movements.  The eyes do not move properly in response to stimuli or voluntarily.  When affected infants are asked to fixate on an object to the side, their eyes will lag and then move in the opposite direction.  In order to compensate for this, the infants will sharply jerk their heads past the desired object in an effort to bring the eyes to a position where they can view the object.  When the eyes fixate on the object, the head will return to its normal position.  These jerking head movements are the most noticeable sign of Cogan type ocular motor apraxia and are usually recognized three to four months after birth.  Before these head jerkings occur, an infant’s inability to fixate on an object may sometimes be mistaken for blindness.

Cogan type ocular motor apraxia is a genetic condition for which the inheritance pattern has not been well established.  It is not clear if it is inherited as an autosomal recessive genetic trait or an autosomal dominant genetic trait.

Cogan type ocular motor apraxia affects males approximately twice as often as females.  Symptoms are present at birth (congenital).  The jerking-head movements associated with this disorder usually appear by the third or fourth month of life.  Approximately 50 cases have been reported in the medical literature.

Symptoms of the following disorders can be similar to those of Cogan type ocular motor apraxia.  Comparisons may be useful for a differential diagnosis:

Balint’s syndrome is a rare eye disorder characterized by the inability to voluntarily look at objects to the side (peripherally).  An affected individual may also have trouble grasping objects due to difficulties with hand-to-eye coordination and may be unable to follow objects across the eyes’ field of vision.  Although the exact cause of Balint’s syndrome is not known, it is thought that symptoms may be caused by improper development of part of the brain.


Oculo-auriculo-vertebral spectrum

Oculo-auriculo-vertebral spectrum (OAVS) refers to three rare disorders that many clinicians believe to be intimately related to one another and which represent the range of severity of the same disorder. These disorders are apparent at birth (congenital). As the name suggests, they involve malformations of the eyes, ears and spine.

Oculo-auriculo-vertebral spectrum represents three rare disorders that are apparent at birth (congenital), and are characterized by a wide spectrum of symptoms and physical features that may vary greatly in range and severity from case to case.  However, such abnormalities tend to involve the cheekbones, jaws, mouth, ears, eyes, and/or bones of the spinal column (vertebrae).  In about 60 percent of the cases, such malformations involve one side of the body (unilateral).  Yet, in approximately 10 to 33 percent of affected individuals, both sides of the body may be involved (bilateral), with one side usually more affected than the other (asymmetry).  In many such cases, the right side is more severely affected than the left.

In most cases, oculo-auriculo-vertebral spectrum occurs randomly, with no apparent cause (sporadic).  However, in some cases, positive family histories have been identified that have suggested autosomal dominant, or, less frequently, autosomal recessive inheritance.  In addition, many researchers suggest that OAVS may be caused by the interaction of many genes, possibly in combination with environmental factors (multifactorial inheritance).

OAVS affects males more frequently than females by an approximate 3:2 ratio.  There is some disagreement in the medical literature concerning the disorder’s rate of occurrence.  Reported estimates range from one in 3000 to 5000 live births up to one in 25,000-40,000 live births.  Most of the physical characteristics associated with OAVS are apparent at birth (congenital), with the possible exception of facial asymmetry, which may not become apparent until approximately four years of age in many cases.

Symptoms of the following disorders may be similar to those of oculo-auriculo-vertebral spectrum.  Comparisons may be useful for a differential diagnosis:

Treacher Collins syndrome is an extremely rare genetic disorder characterized by distinctive abnormalities of the craniofacial area due to underdevelopment (hypoplasia) of certain portions of the skull (e.g., supraorbital rims and zygomatic arches) and lower jaw.  Although the symptoms and physical characteristics associated with Treacher Collins syndrome may vary greatly in severity from case to case, craniofacial abnormalities tend to involve the cheekbones, jaws, mouth, ears, and/or eyes.  Such craniofacial malformations may include underdeveloped (hypoplastic) or absent cheekbones; an incompletely developed, abnormally small lower jaw (mandibular hypoplasia and micrognathia); an unusually large mouth (macrostomia); malformations of the roof of the mouth (palate); and/or dental abnormalities such as misaligned teeth (malocclusion).  Affected infants may also have underdeveloped (hypoplastic) and/or malformed (microtic) outer ears with blind ending or absent external ear canals (atresia), resulting in hearing impairment (conductive hearing loss).  In addition, infants with the disorder may have downwardly slanting eyelid folds (palpebral fissues), partial or total absence of tissue (colobomas) from the outer third of the lower eyelids, and/or additional eye abnormalities.  In approximately 40 percent of cases, Treacher Collins syndrome has autosomal dominant inheritance.  However, in about 60 percent of cases, a positive family history is not found.  Research suggests that such cases represent new genetic changes (mutations) that occur randomly, with no apparent cause (sporadic).  (For more information on this disorder, choose Treacher Collins as your search term in the Rare Disease Database.)


Oculo-Dento-Digital Dysplasia

Oculo-dento-digital dysplasia is a rare disorder that may be inherited as an autosomal dominant trait or be caused by a new change in the genes that occurs for no apparent reason (mutation). There also have been a few instances in which it is thought to have been inherited as an autosomal recessive trait. Major symptoms of cculo-dento-digital dysplasia are webbing of the fourth and fifth fingers, an abnormally small transparent part of the eye (microcornea), a slender nose with narrow nostrils, underdevelopment of the outer flaring wall of each nostril (alae), defective enamel and dry hair that grows slowly.

Oculo-dento-digital dysplasia is a rare disorder characterized by webbing of the fourth and fifth fingers, an abnormally small transparent front part of the eye (cornea),  a slender nose, underdeveloped outer walls of each nostril, narrowing of the nostrils, defective enamel of the teeth and dry hair that grows slowly.

Oculo-dento-digital dysplasia may be inherited as an autosomal dominant trait.  In these cases, it occurs as a result of a change (mutation) in a gene on the long arm of chromosome 6 (6q21-q23.2).  An autosomal recessive form is also thought to exist, but the associated gene has not been identified.

Oculo-dento-digital dysplasia is a very rare disorder that appears to affect males and females in equal numbers.  There have been approximately eighty-five cases reported in the medical literature.

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

Amelogenesis imperfecta is a rare genetic disorder characterized by a developmental defect of the tooth enamel.  Secondary effects of this disorder may be early tooth loss, heightened susceptibility to disease of the tissues surrounding the teeth and increased sensitivity of the teeth to hot and cold. There are multiple types of this disorder and it is inherited through various modes of transmission.  (For more information on this disorder, choose Amelogenesis Imperfecta as your search term in the Rare Disease Database.)

Patients with oculo-dento-digital dysplasia may benefit from surgery to repair the webbed fingers and bone malformations.


眼脑色素沉着不足综合征，Cross型

Oculocerebral Syndrome with Hypopigmentation

oculocerebral syndrome hypopigmentation syndrome, Cross type

Oculocerebral syndrome with hypopigmentation is an extremely rare genetic disorder characterized by the lack of normal color (hypopigmentation) of the skin and hair and abnormalities of the central nervous system that affect the eyes and certain parts of the brain (oculocerebral).

Oculocerebral syndrome with hypopigmentation, also known as Cross syndrome, is an extremely rare genetic disorder that may be apparent at birth (congenital) or during early infancy.

The gene involved in this syndrome is not yet known, but one report suggested that the gene associated with this condition is located on chromosome 3 at 3q27.1q29.

Oculocerebral syndrome with hypopigmentation is an extremely rare disorder that affects males and females in equal numbers. It was first reported in 1967 and, as of 2024, fewer than 20 cases have been described, without an ethnic preference. Most reported cases occurred within families.

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

Chediak-Higashi syndrome is a rare inherited disorder characterized by the lack of normal color of the skin and eyes (oculocutaneous albinism), visual difficulties, and/or abnormalities affecting certain white blood cells (leukocytes) that may result in immune system deficiencies. The hair is typically blond or light brown with a silvery tint. Affected infants may also have abnormal sensitivity to light (photosensitivity), rapid involuntary eye movements (nystagmus) and/or an impaired ability to coordinate voluntary movements (ataxia). Chediak-Higashi syndrome is inherited in an autosomal recessive pattern. (For more information on this disorder, choose Chediak Higashi as your search term in the Rare Disease Database.)

There is no cure or specific treatment. The treatment is symptomatic and supportive, and it is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, dentists, physicians who specialize in disorders of the eyes (ophthalmologists), physicians who specialize in skin disorders (dermatologists), and other health care professionals may need to plan an affected child’s treatment systematically and comprehensively.


Oculocerebrocutaneous syndrome

Oculocerebrocutaneous (OCC) syndrome is a rare genetic disorder that is apparent at birth (congenital). The disorder is characterized primarily by eye (ocular), brain (e.g., cerebral) and skin (cutaneous) malformations. For example, many affected infants have semisolid or fluid-filled swellings (cysts) within the cavities of the skull (orbits) that accommodate the eyeballs and associated structures. In most patients, the eye on the affected side or sides is also abnormally small (microphthalmos). Brain abnormalities associated with OCC syndrome may include enlargement of the ventricular system, multiple fluid-filled spaces within and malformations of the outer region of the cerebral hemispheres (cerebral cortex), absence of the band of nerve fibers that joins the brain’s hemispheres (agenesis of the corpus callosum) and a typical malformation of mid- and hindbrain. Affected infants and children often have intellectual disability and episodes of uncontrolled electrical activity in the brain (seizures). In addition, OCC syndrome is characterized by underdevelopment or absence of skin in certain localized regions (focal dermal hypoplasia or aplasia), and most have protruding, flesh-colored or brownish outgrowths of skin (cutaneous tags) within certain facial areas, including around the eyelids, on the cheeks, or near the ears. In all individuals with OCC syndrome known so far, the disorder occurs sporadically (with no family history of similar disorders).

OCC syndrome is characterized by distinctive eye (ocular), brain (e.g., cerebral) and skin (cutaneous) malformations. Most infants with the disorder have fluid-filled or semisolid swellings (cysts) within the cavities of the skull (orbits) that accommodate the eyeballs. The eye on the affected side or sides is characteristically small (microphthalmos). In some patients, the orbital cysts may contain benign (noncancerous), tumor-like nodules (hamartomas) consisting of ocular tissue. Affected infants may have additional ocular abnormalities, such as absence or defects (notches) of tissue (colobomas) of the upper eyelids, the lower eyelids, or the colored part of the eye(s) (irises) or abnormal persistence of the embryonic blood vessel (the hyaloid artery system) that supplies certain regions of the eyes (persistent fetal vasculature, the hyaloid artery usually disappears during the ninth month of fetal development.)

In all reported individuals with OCC syndrome, there is no family history of the disorder. Therefore, geneticists suggest that OCC syndrome is caused by a genetic change (variant or mutation) that appears to be present in some of the cells of the body only (somatic mosaicism) and is thought to be the consequence of a randomly occurring, new event in one of the cells present at a very early embryonic stage.

OCC syndrome has been reported more frequently in males than in females; however, the prevalence is unknown. Since the disorder was originally described in 1981 (JW Delleman & JWE Oorthuys), approximately 40 patients have been reported in the medical literature.

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

Microphthalmia with linear skin defects syndrome is a rare genetic disorder that is caused by an alteration on the X chromosome (most often a missing piece in chromosome region Xp22.2 that includes the HCCS gene) which affects only females. The disorder is characterized by eye (ocular) defects, including abnormally small size of the eyes (microphthalmia); and clouding of the front, usually transparent surface of the eyes (corneal opacities). These ocular defects typically occur in association with underdevelopment or absence of skin in streak-like (linear) patterns, primarily affecting the head and neck region and healing into hyperpigmented areas with age. Some affected females may have additional abnormalities, including congenital heart defects, a small head (microcephaly), absence of the band of nerve fibers that joins the two hemispheres of the brain (agenesis of the septum pellucidum), seizures, or intellectual disability.


Oculocutaneous albinism

Oculocutaneous albinism (OCA) is a group of rare inherited disorders characterized by a reduction or complete lack of melanin pigment in the skin, hair and eyes. These conditions are caused by mutations in specific genes that are necessary for the production of melanin pigment in specialized cells called melanocytes. Absent or insufficient melanin pigment results in abnormal development of the eyes, resulting in vision abnormalities, and light skin that is very susceptible to damage from the sun including skin cancer. Visual changes include nystagmus (involuntary side to side eye movement), strabismus and photophobia (sensitivity to light). Other changes include foveal hypoplasia (which affects visual acuity) and mis-routing of the optic nerves. All individuals with OCA have the above visual changes but the amount of skin, hair and iris pigment can vary depending on the gene (or type of OCA) and mutation involved.

Several vision problems can occur with this condition including an involuntary movement of eyes back and forth (nystagmus), reduced iris pigment (iris transillumination), reduced retinal pigment, lack of development of the macula (macular hypoplasia) resulting in abnormal foveal development (the area of the eye responsible for visual acuity), poor visual acuity, and abnormal connections in the nerves from the retina to the brain that prevents the eyes from tracking together (strabismus) and reduces depth perception. Visual acuity in individuals can range from 20/60 to 20/400, usually depending on the amount of pigment present in the eye. Vision acuity is usually better in those individuals with greater amounts of pigment.

Melanin pigment is the major pigment responsible for coloration of skin, hair and eyes. There are two types of melanin pigment, brown-black eumelanin and yellow-red pheomelanin. All melanin pigment is a combination of these two types of pigment. Melanin pigment is produced in specialized cells called melanocytes. Mutations in genes responsible for the proteins that are necessary for the melanocyte to make melanin pigment result in a reduction or absence of melanin pigment in the skin, hair and eyes of the affected individual and this condition is termed oculocutaneous albinism (OCA). OCA is inherited as an autosomal recessive genetic condition. Recessive genetic disorders occur when an individual inherits an abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

The frequency of OCA1 is approximately 1/40,000 in the world population. Most of the individuals identified with OCA1 have OCA type 1A. The frequency of OCA type 1B is unknown.

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

Hermansky-Pudlak syndrome is a rare, hereditary disorder that consists of three characteristics: reduced skin, hair and eye pigmentation (oculocutaneous albinism, with associated vision problems), blood platelet dysfunction leading to prolonged bleeding, and abnormal storage of a fatty-like substance (ceroid lipofuscin) in various tissues of the body. Several different genes have been associated with Hermansky-Pudlak syndrome. (For more information on this disorder, choose Hermansky as your search term in the Rare Disease Database.)


Oculopharyngeal muscular dystrophy

Although the defective gene that causes OPMD is present at birth, the symptoms usually do not appear until adulthood sometime between 40 and 60 years of age. OPMD is characterized by progressive weakness of certain muscles around the eyes, in the throat, and less commonly in the pelvic and shoulder areas including the muscles of the upper legs and arms.

OPMD may be inherited as an autosomal dominant or recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

OPMD is a rare disorder that affects males and females in equal numbers. The disorder has been reported in approximately 29 countries. The largest grouping (cluster) of cases was reported in French descendents in Quebec, Canada (1 in 1000). Clusters have also been reported in the Bukhara Jews of Israel and a Hispanic population of New Mexico. One published report estimated the prevalence of OPMD in France at 1 in 100,000 individuals.

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

A diagnosis of OPMD is suspected based upon a thorough clinical evaluation, a detailed patient history, and identification of characteristic findings. A diagnosis is confirmed through commercially available blood tests that can detect the specific genetic abnormality associated with OPMD (i.e., mutation of the PABPN1 gene).


Ogden syndrome

Individuals with Ogden syndrome present at different ages and with a wide spectrum of symptoms and severity. Males with Ogden syndrome tend to be affected more severely and may have life-threatening symptoms in infancy. Females with one disease-causing variant in the NAA10 gene can vary from having no symptoms to having the same features as an affected male.

Ogden syndrome is caused by disease-causing variants in the NAA10 gene. This gene encodes for the enzyme N-terminal acetyltransferase 10. This enzyme along with another protein known as NAA15, makes up the N-terminal acetyltransferase A (NatA) complex. The NatA complex aids in the attachment of a chemical group called acetyl-CoA to the first section of proteins. This attachment process is known as acetylation. Acetylation regulates protein stability, interaction, formation and activity. Certain variants in the NAA10 gene change the structure and function of the protein. This change can reduce stability and cause the symptoms of Ogden syndrome. Therefore, the severity of the disease is dependent on the remaining activity of the enzyme.

Ogden Syndrome is a rare genetic disorder that is usually fully expressed in males. Carrier females may have a wide range of symptoms, from asymptomatic to having the same symptoms as affected males. As of 2024, the disorder has been reported in just over 100 individuals. The overall worldwide prevalence is currently unknown. Data is not available to estimate ethnic-based prevalence.

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

Timothy syndrome (TS), also referred to as long QT syndrome type 8 (LQT8), is a rare multisystem genetic disorder affecting the heart and several other organs, including the skeleton, metabolic system and brain. The most relevant heart manifestation of TS is the prolongation of the time required by the heart to complete a cycle of its electrical activity, known as the QT interval. TS belongs to a group of diseases collectively classified as long QT syndrome or LQTS. The QT interval prolongation predisposes patients to a high risk of developing cardiac arrhythmias and experiencing cardiac arrest from a very young age.


Olivopontocerebellar Atrophy

橄榄体脑桥小脑萎缩-耳聋综合征

The term olivopontocerebellar atrophy (OPCA) has historically been used to describe a group of disorders that affect the central nervous system and are termed neurodegenerative diseases because they result in a progressive deterioration of nerve cells in certain parts of the brain. These conditions are characterized by progressive balance problems (disequilibrium), progressive impairment of the ability to coordinate voluntary movements (cerebellar ataxia), and difficulty speaking or slurred speech (dysarthria).

Among the different classifications, there is wide variation in severity and age of onset. The symptoms of OPCA differ from person to person. Most patients experience difficulty with balance and coordination of the legs and arms (ataxia) and slurred speech (dysarthria). Other symptoms may include muscle spasms or weakness and stiffness of the muscles; numbness or tingling of the hands or feet; shaking (tremor) of the hand or arm; reduction or slowness of movements; loss of thinking and/or memory skills; difficulty controlling the bladder or bowels; and feeling faint when standing up. Some patients also have fatigue and/or trouble with sleep. Generally, symptoms of OPCA begin in mid-adult life and progress slowly over the course of many years.

Most types of inherited OPCA are spinocerebellar ataxias that follow autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.

OPCA is a group of rare disorders that affects males and females in equal numbers. Because of confusion regarding the naming and classification of these disorders, determining their frequency in the general population is difficult. The frequency of all forms of OPCA has been estimated to be 3-5/100,000 in the United States.

The following disorders overlap with OPCA. Comparisons may be useful for a differential diagnosis:

Spinocerebellar ataxia (SCA) is a group of neurodegenerative disorders affecting the brainstem and spinal cord. Most follow autosomal dominant inheritance and are usually identified as SCA1 through SCA25. The symptoms of SCA vary between types and among individuals affected with the same type. (For more information on these disorders, choose ataxia, hereditary, autosomal dominant as your search term in the Rare Disease Database.)


Ollier disease

Ollier disease is not always apparent at birth, but symptoms will usually become evident by early childhood. Between the ages of one and four years, abnormal and/or slow growth of arms and legs is often observed. Usually one leg and/or arm is affected, but both legs and/or arms may be involved. If both legs are involved, short stature may result; if only one leg is involved, then an affected individual may limp.

The underlying cause of Ollier disease is not known. Changes (mutations) in IDH1, IDH2 and PTHR1 genes have been linked to Ollier disease and Maffucci syndrome. The mutations are due to somatic mosaicism, which means that the mutation is present only in a percentage of the cells, not all the cells in the body. In Ollier disease, the mutation is present only in the enchondromas.

The estimated prevalence of the disease is 1/100,000. Ollier disease is a very rare disorder that affects males and females in equal numbers. Symptoms are most often observed in children but can occur in adolescents and adults. This disorder can affect all races.

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

Metachondromatosis presents with enchondromas and osteochondroma (exostoses). The enchondromas most commonly involve the long bones of the legs and the hip. The osteochondroma lesions usually appear on the hands and feet. Most of the time, these lesions do not cause bone deformities. There are less than 30 reported cases currently.


Opsoclonus-myoclonus syndrome

Opsoclonus-myoclonus-ataxia syndrome (OMAS) is an inflammatory neurological disorder, often caused by the immune system reacting to a cancerous tumor (paraneoplastic etiology). It is characterized by associated ocular, motor, behavioral, sleep and language disturbances. The onset is usually abrupt, often severe, and it can become chronic.

The component features of OMAS include repeated, random and rapid eye movements in both horizontal, vertical and diagonal directions (opsoclonus); unsteady gait or loss of ability to stand and walk (ataxia); brief, repeated, shock-like spasms of several muscles within the arms and legs (myoclonus), or tremor interfering with hand use. Behavioral and sleep disturbances, including extreme irritability, inconsolable crying, reduced and fragmented sleep (insomnia) and rage attacks are common. Difficulty articulating speech (dysarthria), sometimes with complete loss of speech and language may occur. Additional symptoms such as decreased muscle tone (hypotonia) and vomiting are common.

The most common cause of OMS in young children is paraneoplastic. A small, often hidden tumor presumably provokes the immune system into attacking the nervous system, which may also control the tumor or even cause it to regress. Tumors are not in the brain, but are in other areas of the body, usually in chest or abdomen. In 50-80% of affected young children, a tumor of embryonic nerve cells (neuroblastoma or ganglioneuroblastoma) is responsible for the symptoms associated with OMS. In other affected individuals, the disorder has been designated ‘idiopathic’ or attributed to various mostly viral infections. However, the high rate of spontaneous tumor regression means that the tumor may be gone before it is looked for. In older children or teens, viral infections are the most frequent apparent cause of OMAS. In adults, paraneoplastic etiology is more common, mostly due to lung or breast cancers. In contrast to paraneoplastic OMAS in infants and young children, whose tumors are biologically inactive and often benign, the tumors in adults are commonly malignant, often disseminated.

OMAS is a rare disorder with a prevalence of 1 per million individuals worldwide. It usually affects infants and young children, although it is also known to affect adults. The peak age in children is about 18 months, with very few diagnosed before 1 year, and a few children diagnosed between 5–6 years. Occurrence of opsoclonus in infants under 6 months old is quite uncommon, and opsoclonus in that age group, when isolated, is usually from another cause. OMAS occurs slightly more often in girls than boys. It occurs in about 3% of all children with neuroblastomas.

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

About 95% of children with OMAS are initially diagnosed as having acute cerebellar ataxia, a much more common disorder. In children with OMAS, the ataxia may appear before the eye findings. This diagnosis may cause delay in recognition and treatment of OMAS. Once opsoclonus is present, however, the diagnosis cannot be acute cerebellar ataxia. Also, children with only occasional or subtle opsoclonus or myoclonus are harder to recognize and may carry the wrong diagnosis for years.


Septo-optic dysplasia spectrum

透明隔-视神经发育不良疾病谱

ONH is present at birth, but many symptoms may not be apparent until childhood, or even adolescence. Most infants with ONH have involuntary, rapid eye movements (nystagmus) and/or mild to severe visual impairment of one or both eyes. Vision often improves modestly in early childhood even though there is no growth of the optic nerves after birth. Due to underdevelopment of the optic nerves, the optic disk is smaller than normal size in one or both eyes when viewed by a doctor using an ophthalmoscope. Also referred to as the blind spot, the optic disk is the structure in which nerve fibers from the retina combine to form the optic nerve before leaving the back of the eye. The optic nerves meet to form the optic chiasm and optic tracts at the base of the hypothalamus.

The cause of ONH is not known. In most cases, the disorder appears to occur randomly for unknown reasons (sporadic). Rare families have been reported with more than one affected child, suggesting the possibility of autosomal recessive inheritance. A few cases of SOD have been reported to result from a mutation HESX1, SOX2, SOX3, OTX2 or PROKR2 genes. The diagnosis of SOD has been loosely defined in these cases, with the majority having normal optic nerves or ocular malformations other than ONH. The vast majority of individuals with ONH do not have mutations in any of these genes, suggesting that other genes and/or environmental factors are involved in the development of this condition.

ONH is thought to affect males and females in equal numbers. The prevalence is estimated to be 1 in 10,000 children.

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

Holoprosencephaly (HPE) is the failure of the prosencephalon (a region of the brain in the fetus that develops into parts of the adult brain), or forebrain, to develop normally. Instead of the normal completely distinct left and right halves of the forebrain, there is an abnormal continuity between the two sides. Intellectual disability is associated and seizures are often present. Children with holoprosencephaly may also have defects in the development of the middle of the face such as closely set eyes (hypotelorism), tooth abnormalities (single central incisor), cleft lip/palate, and an abnormally small head (microcephaly). (For more information on this condition, choose holoprosencephaly as your search term in the Rare Disease Database.)


Oculofaciocardiodental syndrome

Oral-facial-digital syndrome (OFDS) is a group of conditions that affect the development of their oral cavity (mouth, tongue, teeth, and jaw), face (head, eyes and nose) and finger and toes (digits).

The various types of OFDS present with some combination of signs and symptoms from the list below.

Chromosomes, which are present in the nucleus of human cells, carry the genetic information (DNA) for each individual. The genetic information is carried in genes. Harmful gene changes (mutations) can cause the gene to not properly. This can lead to genetic conditions.

All types of oral-facial-digital syndrome are rare, with type I being the least rare. The incidence of OFDS type I is thought to be between 1 per 50,000 births and 1 per 250,000 births, and type II is thought to occur 1 in 300,000 births. Some types of OFDS have only been reported in a few people/families.

Symptoms of the following conditions can be similar to those of OFSD syndrome. Comparisons may be useful to help make a diagnosis:

Diagnosis of OFD syndromes with a known genetic cause (OFDS type I, III, IV, V, VI, IX, XIV) can be confirmed by genetic testing. However, diagnosis is generally made based on the clinical symptoms presented.


Organizing Pneumonia

Organizing pneumonia (OP) is a rare inflammatory lung disorder characterized by clinical symptoms such as flu-like illness as well as cough and shortness of breath with exertional activities. Wheezing and hemoptysis (blood when coughing) may occur rarely. OP refers to organized swirls of inflammatory tissue filling the small spherical units of the lungs called alveoli as well as the alveolar ducts. Individuals with OP experience inflammation of the bronchioles and alveolar lung spherical units simultaneously, which distinguishes it from other similar inflammatory lung disorders. Though the term pneumonia is used, OP is not an infection. It is a different disease from obliterative bronchiolitis which refers to scarring and narrowing of the small airways.

Symptoms of organizing pneumonia vary from person to person depending upon the specific type. For example, people with idiopathic OP have a flu-like illness, while people with OP associated with an underlying connective-tissue disorder have cough or shortness of breath. Some individuals with OP such as focal OP may have no apparent symptoms, while others may have severe respiratory distress as in acute, rapidly progressive OP.

In most cases, the cause of OP is unknown and is referred to as idiopathic OP. Causes of OP include radiation therapy; exposure to certain fumes or chemicals, exposure to birds, post respiratory infections, after organ transplantation; and from more than 35 medications. Systemic disorders associated with OP include connective-tissue diseases, immunological disorders and inflammatory bowel disease. Organizing pneumonia has also been seen in association with lung abscess, lung cancer and lymphoma. Importantly, the OP lesion is seen as a co-existent pathologic finding in individuals with idiopathic pulmonary fibrosis (IPF) and in these situations, the primary pathologic disorder is the IPF, and the secondary process is OP.

Organizing pneumonia affects males and females in equal numbers. It develops in individuals between 40-60 years old, but the disorder may affect individuals of any age. Organizing pneumonia is estimated to account for 5 to 10% of the chronic infiltrative lung disease in the United States. Organizing pneumonia has been reported throughout the world.

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

A diagnosis of OP may be made based upon a clinical evaluation, a detailed patient history, identification of characteristic findings and specialized tests such as x-ray studies, especially a high-resolution chest computed tomography (HRCT), pulmonary function studies that includes a diffusing capacity test and often a lung biopsy for microscopic tissue analysis. Lung biopsy may infrequently be made via conventional transbronchial biopsy, transbronchial cryobiopsy which is newer and recovers a larger bit of tissue, or in selected cases, open lung biopsy. The HRCT scan often shows ground glass densities that are often triangular with the base of the triangle along the chest wall and the airways can often be seen in the ground-glass opacities. There are other less common findings such as inflammation along the air tubes or bronchi as well as single spots or nodules which are sometimes confused with malignancy, or the so-called ‘atoll’ spots which are areas of inflammation with central darker areas on HRCT.


Ornithine transcarbamylase deficiency

鸟氨酸氨甲酰转移酶缺乏症

hyperammonemia due to ornithine transcarbamylase deficiency

Ornithine transcarbamylase (OTC) deficiency is a rare X-linked genetic disorder characterized by complete or partial lack of the enzyme ornithine transcarbamylase (OTC). OTC is one of six enzymes that play a role in the break down and removal of nitrogen the body, a process known as the urea cycle. The lack of the OTC enzyme results in excessive accumulation of nitrogen, in the form of ammonia (hyperammonemia), in the blood. Excess ammonia, which is a neurotoxin, travels to the central nervous system through the blood, resulting in the symptoms and physical findings associated with OTC deficiency. Symptoms include vomiting, refusal to eat, progressive lethargy, and coma.

The severity and age of onset of OTC deficiency vary from person to person, even within the same family. A severe form of the disorder affects some infants, typically males, shortly after birth (neonatal period). A milder form of the disorder affects some children later in infancy. Both males and females may develop symptoms of OTC deficiency during childhood. Most carrier females are healthy, but may be prone to severe headaches following protein intake.

OTC deficiency is inherited as an X-linked genetic condition. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have a defective gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the defective gene. However, approximately 20% of female carriers of the OTC gene are symptomatic. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a defective gene he will develop the disease. Many males with OTC deficiency have an abnormal OTC gene as the result of a new mutation as opposed to a mutation inherited from the mother.

OTC deficiency affects males more often than females and is fully expressed in males only. In males, symptoms typically begin during the first few days of life. Late-onset OTC deficiency can present later in childhood, but may also occur with onset at 40-50 years of age. Approximately 20% of carrier females have mild symptoms of the disorder and rarely may be severely affected in childhood. Some women who are carriers may not experience abnormally high levels of ammonia (hyperammonemia) until pregnancy or delivery.

Symptoms of the following disorders can be similar to those of ornithine transcarbamylase 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 individuals, life-threatening complications may result. In addition to OTC deficiency, the other urea cycle disorders are: carbamyl phosphate synthetase (CPS) deficiency; argininosuccinate synthetase deficiency (citrullinemia); argininosuccinate lyase (ASL) deficiency; arginase deficiency (argininemia); and N-acetylglutamate synthetase (NAGS) deficiency. (For more information on these disorders, choose the specific disorder name as your search terms in the Rare Disease Database.)


Juberg-Hayward syndrome

Cleft Lip/Palate with Abnormal Thumbs and Microcephaly

Orocraniodigital syndrome is an extremely rare inherited disorder characterized by multiple malformations of the head and face (craniofacial area) and the fingers and toes (digits). Major characteristics may include a vertical groove in the upper lip (cleft lip) and/or the inside, upper portion of the mouth (cleft palate), an abnormally small head (microcephaly), widely spaced eyes (ocular hypertelorism), improper development (hypoplasia) of the thumbs and/or toes, and/or webbing (syndactyly) of the toes. In some cases, malformations of certain skeletal bones may also be present. Mental retardation has occurred in the majority of cases. Orocraniodigital syndrome may be inherited as an autosomal recessive genetic trait.

In many cases, orocraniodigital syndrome is characterized by cleft lip and/or palate, malformations of the mouth and/or lips that are noticeable at birth (congenital).  A cleft is an incomplete closure or groove on the inside, upper portion of the mouth (palate) or lips, or both.  Clefts may be barely noticeable (occult), or they may cause severe deformities leading to difficulties in speaking.

Orocraniodigital syndrome is thought to be inherited as an autosomal recessive genetic trait.  However, autosomal dominant inheritance has yet to be ruled out.

Approximately 10 cases of orocraniodigital syndrome have been reported in the medical literature.  The symptoms are usually obvious at birth.

Craniofrontonasal dysplasia is a rare inherited disorder characterized by widely spaced eyes (ocular hypertelorism), a missing or grooved tip of the nose, a broad nasal bridge, and/or malformation of the long flat vertical bone in the center of the chest (sternum).  Other abnormalities associated with this disorder may include an unusually wide mouth, webbed fingers and/or toes (syndactyly), split nails, a broad index finger, malformed (dysplastic) ears, and/or a broad high forehead.  Craniofrontonasal dysplasia is thought to be inherited as an autosomal dominant genetic trait.  (For more information on this disorder, choose Craniofrontonasal Dysplasia as your search term in the Rare Disease Database.)

Orocraniodigital Syndrome is usually diagnosed shortly after birth (neonatal period) based upon a thorough clinical evaluation. Treatment of this disorder depends upon the specifics and severity of each individual case. Surgery may correct some of the craniofacial deformities associated with this disorder. For example, infants with cleft lip may require surgery; in some cases, additional surgery may be necessary when the child grows older. Cleft palate may also be surgically repaired. In some cases, hand and/or feet malformations associated with Orocraniodigital Syndrome may also be surgically corrected.


Orthostatic Hypotension

Orthostatic hypotension (OH) is a common condition characterized as a drop in blood pressure that occurs when a person stands up. OH can cause lightheadedness, dizziness or even causing a person to faint. Symptoms can also be subtle or absent. By definition, the drop in blood pressure must be greater than 20mm Hg of mercury in systolic BP and/or more than 10 mm of mercury in diastolic BP within 3 minutes upon standing from sitting or from a lying down face-up (supine) position. There are numerous, varied causes of OH. Neurogenic orthostatic hypotension (NOH) is a rare subtype caused by underlying neurologic disorders that affect a specific part of the autonomic nervous system. The autonomic nervous system is the part of the nervous system that regulates certain involuntary body functions such as heart rate, blood pressure, sweating, and bowel and bladder control. The treatment of OH depends upon several factors including the specific underlying cause.

In some people, there may not be any noticeable symptoms despite a sudden and extreme drop in blood pressure upon rising from a reclining position. When symptoms occur they can vary greatly in expression from one individual to another. Common symptoms can include dizziness, lightheadedness, generalized weakness, leg buckling, nausea, blurry vision, fatigue, and headaches. Additional symptoms can include chest pain (angina), head and neck pain (often affecting neck and shoulders with a coat hanger distribution), and a decline in cognitive functioning such as difficulty concentrating.

Orthostatic hypotension may be a temporary condition or one that occurs consistently over time (chronic). Some sources break down the causes of OH into drugs, non-neurogenic, primary neurogenic and secondary neurogenic causes. In many cases, the underlying cause of OH remains unknown or unproven (idiopathic). Most idiopathic cases are believed to have an underlying neurogenic cause.

OH is most common in the elderly, postpartum mothers, those who have been on bed rest, and teenagers, because of their large amounts of growth over a small time period. The prevalence increases with age. Institutionalized elderly have higher rates of OH than individuals who remain living in the community.

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

Neurally mediated syncope is a general term for a group of conditions in which sudden change in the activity of the autonomic nervous system results in a fall in blood pressure. Neurally mediated syncope can lead to a temporary loss of consciousness (syncope). Individuals often experience nonspecific symptoms just before the onset of an episode (prodome). Such symptoms include pallor, yawning, sighing, nausea, and abdominal discomfort. This is usually followed by additional symptoms such as difficulty concentrating, cognitive impairment, and disturbances in hearing and or sight. This group of disorders includes vasovagal syncope, which there is a temporary impairment of blood circulation in the brain. It may occur during emotional stress, pain or mild shock. It may also result from prolonged bed rest, anemia, fever, fasting or mild heart disease.


OSMED, Heterozygous

常染色体显性遗传性骨骺发育不良

Oto-Spondylo-Megaepiphyseal Dysplasia, Autosomal Dominant

Heterozygous OSMED (oto-spondyl-megaepiphyseal dysplasia) is a rare genetic disorder characterized by skeletal malformations resulting in shortening of the upper limbs and thighs and short stature (rhizomelic dwarfism). Additional symptoms include distinctive facial features and delays in psychomotor development. After the initial period of growth deficiency, affected individuals experience gradual improvement in bone growth that leads to normal physical development by early childhood. Mental and motor development is also normal by early childhood. In some cases, affected individuals develop hearing loss. Heterozygous OSMED occurs because of disruptions or changes (mutations) to the COL11A2 gene.

Heterozygous OSMED is characterized by skeletal malformations, distinct facial features and delayed psychomotor development. The specific symptoms affecting each child vary from case to case.

Heterozygous OSMED is inherited as an autosomal dominant trait. Some cases occur randomly as the result of a spontaneous genetic change (i.e., new mutation). 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.

Heterozygous OSMED affects males and females in equal numbers. Both heterozygous and homozygous OSMED are extremely rare; approximately 30 cases have been reported in the medical literature. The exact incidence of this disorder is unknown. These disorders may be underdiagnosed making it difficult to determine their true frequency in the general population.

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

A diagnosis of heterozygous OSMED is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms, and a variety of specialized tests including x-rays. X-ray studies reveal characteristic skeletal malformations associated with heterozygous OSMED.


Osteochondritis dissecans

Symptoms of osteochondritis dissecans are often vague and occur on and off especially in early stages of the condition but may increase with activities such as climbing stairs or throwing. As the condition progresses and more loose bits of cartilage and bone are found in the joint, there may be catching (partial inhibition of movement), locking, (total inhibition of movement) or a sense of giving way of the joint and there may also be the sensation of loose fragments within the joint. Additionally, there may be pain and swelling of the affected joint.

Osteochondritis dissecans is estimated to be 2-3x more common in males and more common in people aged 10-15 (average = 11.3-13.4 years). It affects fewer than 30 people per 100,000. It is rarer for patients older than 50 or younger than 10 to develop this condition. While OCD most commonly affects the knees, boys tend to have a higher risk of developing osteochondritis dissecans in the knees or elbows whereas girls have a higher risk of developing it in the ankles.

Osteochondritis dissecans may be part of an inherited condition such as genetic forms of short stature (dwarfism), bow-legging (tibia vara), Legg-Calvé-Perthes disease and Stickler’s syndrome.

As mentioned above, the physical exam findings in a person with osteochondritis dissecans are often not specific enough to confirm a diagnosis. Therefore, diagnosis is mostly reliant on imaging. Initial imaging of the joint is usually conducted with x-rays that may show transparency of subchondral bone, separation of bone fragments from underlying bone, evidenced by a dark (radiolucent) line, or loose osseous bodies. On further imaging such as an magnetic resonance imaging (MRI), physicians may be able to better characterize the state of the bone and cartilage, determine the degree of displacement of those pieces and monitor treatment progress or restoration of vascular supply. Studies have shown that MRI and arthroscopy (surgical visualization of the inside of the joint with a camera) are the best tools to determine disease diagnosis and progression.


Osteogenesis imperfecta

Osteogenesis imperfecta (OI) is a rare disease affecting the connective tissue and is characterized by extremely fragile bones that break or fracture easily (brittle bones). The abnormal growth of bones is often referred to as a bone dysplasia. The specific symptoms and physical findings associated with OI vary greatly from person to person. The severity of OI also varies greatly, even among individuals in the same family. OI may be a mild disorder or result in severe complications.

In all types of osteogenesis imperfecta, symptoms vary greatly from one individual to the next, even within the same type and the same family.  Some affected individuals may not experience any bone fractures or only a few. Other affected individuals experience multiple fractures. The age of onset of fractures varies from person to person. OI is a collagen related disease, and as such, the arrangement and integrity of teeth (dentition), lung function, heart (cardiac) function, muscle strength and ligament flexibility may be affected as well.

Osteogenesis Imperfecta types I through IV are caused by mutations in the COL1A1 or COL1A2 genes. These genes carry instructions for the production of type 1 collagen. Collagen is the major protein of bone and connective tissue including the skin, tendons and sclera. The collagen protein is made up of three strands of proteins (two alpha 1 strands and one alpha 2 strand) that wind together in a helical fashion. These helical molecules then pack side by side to form characteristic bands that are linked together.  This structure gives collagen enormous tensile strength. When a mutation occurs, the collagen that the mutated gene produces may be faulty or insufficient.  In type I, the gene mutation results in a normal collagen protein, but only one-half of the normal amount is produced. Types II through IV are the result of mutations that affect the structure of the collagen protein. The precise location and type of mutation determines the severity of the resulting disease. The non-collagen types of OI (types V-XXI) are caused by mutations in genes that code for other proteins that play a pivotal role in the production of normal collagen.

Osteogenesis imperfecta affects males and females in equal numbers.  The incidence of cases recognizable at birth is 1:10-20,000. More mild types that are only recognized later in life occur at about the same incidence. It is estimated that 20,000 to 50,000 individuals in the United States have OI.

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

Achondroplasia is a skeletal dysplasia characterized by short stature, abnormally short arms and legs (short-limbed dwarfism), abnormal facial features and skeletal malformations. Characteristic facial features may include an abnormally large head (macrocephaly), unusual prominence of the forehead (frontal bossing), a low nasal bridge and underdevelopment of the middle portion of the face (midface hypoplasia).  Skeletal malformations may include unusually short fingers and toes (brachydactyly), an increased concave curvature of the lower spine (lordosis), legs that bow outward (genu varum) and/or narrowing (stenosis) of the spine.  Additional abnormalities may include limited extension of the elbows and hips, diminished muscle tone (hypotonia) and/or frequent infections of the middle ear (otitis media). Achondroplasia is caused by a mutation in the FGFR3 gene. Eighty percent of cases are sporadic, and it is inherited in an autosomal dominant manner. (For more information on this disorder, choose achondroplasia as your search term in the Rare Disease Database.)


Osteonecrosis

Osteonecrosis, also known as avascular necrosis (AVN), aseptic necrosis or ischemic bone necrosis, is a disease resulting in the death of bone cells. If the process involves the bones near a joint, it often leads to collapse of the joint surface and subsequent arthritis due to an irregular joint surface. The exact cause is unknown.

In the early stages of osteonecrosis, patients may not have any symptoms. As the disease progresses, however, most patients experience joint pain – at first, only when putting weight on the affected joint, and then even when resting. Pain usually develops gradually and may be mild or severe. If osteonecrosis progresses and the bone and surrounding joint surface collapse, pain may develop or increase dramatically. Pain may be severe enough to cause joint stiffness by limiting the range of motion in the affected joint. Disabling osteoarthritis may develop in the affected joint. The period of time between the first symptoms and loss of joint function is different for each patient, ranging from several months to more than a year.

Osteonecrosis has many different causes. Loss of blood supply to the bone may lead to bone cell death and can be caused by an injury (bone fracture or joint dislocation; called traumatic osteonecrosis). At times, there may be no history of injury (non-traumatic osteonecrosis); however, other risk factors are associated with the disease such as some medications (steroids, also known as corticosteroids), alcohol usage or blood coagulation disorders. Increased pressure within the bone also is associated with osteonecrosis. One theory is that the pressure within the bone causes the blood vessels to narrow, making it difficult for blood to circulate through the bone. Osteonecrosis can also be associated with other disorders. The exact reason osteonecrosis develops is not fully understood for some risk factors. Sometimes, osteonecrosis occurs in people with no risk factors (idiopathic). Some people have multiple risk factors. Osteonecrosis most likely develops because of the combination of factors, possibly including genetic, metabolic, self-imposed (alcohol, smoking), and other diseases that you may have and their treatment.

Osteonecrosis usually affects people between 30 and 50 years of age; about 10,000 to 20,000 people develop osteonecrosis each year in the United States. Osteonecrosis affects both men and women and affects people of all ages. It is most common among people in their thirties and forties. Depending on a person’s risk factors and whether the underlying cause is trauma, it also can affect younger or older people.

Symptoms of the disorders listed below may be similar to those of osteonecrosis. Comparisons may be useful for a differential diagnosis:

Osteopetrosis is a combination of several rare genetically caused symptoms grouped together as one disorder. It can be inherited and is marked by increased bone density, brittle bones, and, in some people, skeletal abnormalities. Although symptoms may not initially be apparent to people with mild forms of this disorder, trivial injuries may cause bone fractures due to abnormalities of the bone. The dominantly transmitted form is milder than the recessive form and may not be diagnosed until adolescence or adulthood when symptoms first appear. More serious complications occur in the recessive form which may be diagnosed from examination of skeletal x-rays during infancy or childhood. (For more information on this disorder, choose Osteopetrosis as your search term in the Rare Disease Database.)


Osteopetrosis

Osteopetrosis is characterized by overly dense bones throughout the body. Symptoms include fractures, low blood cell production and loss of cranial nerve function causing blindness, deafness and/or facial nerve paralysis. Affected individuals may experience frequent infections of teeth and the bone in the jaw.

Osteopetrosis can be inherited in either an autosomal dominant or recessive pattern, and extremely rarely, in an X-linked recessive pattern. The basic defect in bone reabsorption is an insufficient production or defective function of cells called osteoclasts. These cells are responsible for bone resorption and aid in the maintenance of healthy bone, which relies on a balance between bone resorption (by osteoclasts) and bone formation (by other specialized cells called osteoblasts). The human skeleton is completely regenerated every 10 years. In this context, osteoclasts are essential for bone turnover (replacement of old bone by new bone), bone remodeling as well as micro-fracture repair.

Approximately eight to 40 children are born in the United States each year with the malignant infantile type of osteopetrosis. In the general population, one in every 250,000 individuals is born with this form of osteopetrosis. Higher rates have been found in specific regions of Costa Rica, the Middle East, Sweden and Russia. Males and females are affected in equal numbers.

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

Melorheostosis is a rare disorder resulting from abnormal development of the outer layer of the bone (cortex) which becomes hyperdense and widened. It also affects the surrounding soft tissues. It is characterized by deformity of one or more limbs, with pain and restriction of movement of the affected limb. It usually occurs sporadically. (For more information on this disorder, choose melorheostosis as your search term in the Rare Disease Database.)


Osteosarcoma

Osteosarcoma is a form of cancer. It is a type of tumor that affects the bones. Osteosarcoma can affect people of any age but is most common during the teen-aged years and is the most common bone cancer affecting children and adolescents under the age of 20. The long bones of the legs, usually near where they connect to the knees, and the upper long bone of the arms, near where this bone meets the shoulders are the most common sites for osteosarcoma formation. Symptoms will vary depending upon the exact location and extent of disease. Pain is the most common symptom of osteosarcoma and there is often a mass or bump that can be felt (palpable). Eighty percent of individuals present with localized disease, which means the cancer remains in the area it first developed. Osteosarcoma can spread (metastasize) to other areas of the body, most likely the lungs. The exact cause is unknown in most individuals, but osteosarcoma can be induced by radiation. Most individuals are treated with a combination of chemotherapy and surgery. Sometimes, radiation therapy may be used.

The most commonly affected bones are the long bones of the legs. These are the femur and the tibia. The femur, also called the thighbone, runs from the hip to the knee, and the tibia, or shinbone, runs from the knee to the ankle. The femur and the tibia meet at the knee where they help to form the knee joint. Osteosarcomas can form where these bones are growing the fastest in children and adolescents, which is called the growth plate. About 50% of individuals develop an osteosarcoma around the knee. For the legs this is near the knees and includes the bottom of the femur and the tops of the tibia. Osteosarcomas can also affect the upper part of the long bone of the arms called the humerus. The humerus runs from the elbow to the shoulder. The area near where the humerus connects to the shoulder accounts for about 15% of osteosarcomas.

As with many forms of cancer, the exact, underlying cause of osteosarcoma is unknown in most individuals. In most children and adolescents, this cancer is thought to occur randomly, for no specific reason (sporadically). Sporadic occurrence of cancer is thought to occur because of multiple factors acting together. This can include genetic and environmental factors. The cancerous cells in osteosarcomas are usually mesenchymal stem cells or osteoblasts. Mesenchymal stem cells are adult stem cells that can grow and change (differentiate) into different types of cells including bone, cartilage, muscle, fat, or connective tissue. Osteoblasts are cells that work to develop new bone. When they become cancerous, they may produce an immature form of bone called an osteoid, which is how the pathologist makes the diagnosis.

There are estimated to be about 750-1,000 people diagnosed with osteosarcoma each year in the United States. About 450 of those are children or adolescents under the age of 20. Osteosarcoma is a rare disorder, but it is the most common cause of bone cancer in children and adolescents. These tumors usually affect individuals in their second decade of life (10-19 years of age), most often between 13 and 16 years of age, which most likely coincides with adolescent growth spurts. There is a second increase in the number of people with osteosarcoma in people over the age of 60. Overall, osteosarcoma accounts for about 1% of all cancers diagnosed each year in the United States. Osteosarcoma affect slightly more males than females and is slightly more common in African Americans and Hispanics/Latinos than in Caucasians.

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

A diagnosis of osteosarcoma is suspected upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A physical examination may reveal swelling or a mass that is tender to the touch, and limited mobility of a nearby joint.


Otopalatodigital Syndrome Type I and II

Otopalatodigital syndromes type I and II are rare X-linked genetic disorders in which complete expression of the disease occurs only in males. Females may be affected with some of the symptoms. OPD type I is the milder form of the disease and is characterized by cleft palate, hearing loss and skeletal abnormalities in the skull and limbs. OPD type II includes these abnormalities as well as growth deficiency and, in a minority, abnormalities of the brain and is frequently not compatible with life.

Individuals with OPD type I typically have short stature, an incomplete closure of the roof of the mouth (cleft palate), a downward slant of the opening between the upper and lower eyelids, hearing loss due to a defect of the middle ear (conductive hearing loss), and abnormal shortness of the fingers and toes. Symptoms that are sometimes seen in OPD type I are: short, broad thumbs and great toes; wide spaces between the toes; one or more fingers bent to the side; two or more digits united (syndactyly); short fingernails; dislocation of the head of the radius (one of the bones of the forearm); a broad bridge of the nose; underdeveloped bones of the face; and/or slow speech development. Females with the disorder may have an overhanging brow, a depressed nasal bridge, a wide space between the eyes, and a flat midface. The symptoms expressed in females vary and are fewer. Females do not have the full expression of this disorder.

OPD type I and II are caused by mutations in the FLNA gene on the X chromosome which is responsible for production of the filamin (FLNA) protein. Different mutations in the FLNA gene are responsible for the two syndromes. The filamin protein is normally responsible for helping with the formation and function of the cell’s cytoskeleton, and the mutations appear to give filamin a new function (referred to as a gain-of-function mutation) that leads to OPD type I and II.

OPD type 1 and II are rare disorders affecting less than 1 in every 100,000 individuals. The specific incidence for these conditions is unknown.

Symptoms of the following disorders can be similar to those of otopalatodigital syndrome type I and II. Comparisons may be useful for a differential diagnosis:

The diagnosis of OPD type I or II is based on physical features and X-ray findings. Clinical molecular genetic testing for mutations in the FLNA gene is available to confirm the diagnosis. Skeletal abnormalities associated with these conditions can sometimes be seen on a prenatal ultrasound exam.