Q fever

The symptoms of Q fever can vary dramatically from one person to another. Infection can result in no apparent symptoms (asymptomatic); an acute form of disease characterized by a flu-like illness that either goes away on its own (self-limited) or causes more serious symptoms; or a chronic form that can be associated with serious complications. Researchers believe that a variety of factors may influence the severity of Q fever including age, gender and a person’s general health, including pre-existing medical conditions (e.g., heart disease).

Q fever is caused by inhalation or ingestion of the bacterium Coxiella burnetii. People are most often exposed to the bacterium from the milk, urine and feces of infected animals (for example, by inhaling contaminated air in a barnyard). When these waste substances dry in the air, the bacteria are able to mix with the barnyard dust that floats around. Consequently, this infection is primarily transferred to humans through their lungs when they breathe the contaminated dust.  Also, when an infected animal gives birth, the bacteria may be present in high numbers in the amniotic fluid and placenta. Q fever bacterium primarily infects farm animals such as cattle sheep and goats. However, it has been reported in a wide variety of animals including domesticated animals such as dogs, cats and rabbits. The C. burnetii bacterium is highly infectious. The bacterium can survive in the environment for lengthy periods of time because it is resistant to environmental conditions such heat and pressure. It is also resistant to many common disinfectants.

Q fever occurs worldwide and can affect individuals of every racial and ethnic background. The incidence of Q fever is unknown because in many countries it is not a reportable disease.  Researchers believe that the infection is underreported. From 2000-2012, the incidence rate for this disease in the United States was 0.38 cases per million people per year. There have been higher incidence rates in certain countries such as the Netherlands, where there were reports of thousands of human cases.

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

The signs and symptoms of Q fever are nonspecific and can be associated with a wide variety of diseases. A diagnosis of Q fever usually requires serological examination, which measures and characterizes antibodies. Q fever has two antibody-producing (antigenic) phases called phase I and phase II. These phases can help confirm a diagnosis and can help distinguish acute Q fever infection from chronic Q fever infection. Infected individuals develop specific antibodies against Q fever including immunoglobulin G (IgG), immunoglobulin A (IgA) and immunoglobulin M (IgM). Measuring the levels of these classes of antibodies can help confirm a diagnosis of Q fever. During the acute phase of Q fever, IgG and IgM antibodies may be detected. In chronic Q fever, IgG or IgA levels may be detected.

Antibiotic therapy is used to treat individuals with Q fever. Some mild cases of Q fever may improve without treatment, although antibiotic therapy can usually help reduce the duration of the infection. Physicians recommend that all individuals in whom Q fever is detected receive antibiotic therapy, even those with no recognizable symptoms.


Rabies

Rabies is an infectious disease that can affect all species of warmblooded animals, including man. This disorder is transmitted by the saliva of an infected animal and is caused by a virus (Neurotropic lyssavirus) that affects the salivary glands and the central nervous system. The symptoms may lead to serious complications if the virus is not treated immediately.

The symptoms of rabies usually develop within 20-60 days after a bite or scratch from an animal infected with the rabies virus.  The incubation period is the time between the exposure and the appearance of the first neurologic symptoms.  The incubation period is usually shorter when the sight of exposure is closer to the brain.  The initial symptoms may be a general feeling of discomfort or uneasiness, nervousness, anxiety, insomnia, depression, loss of appetite, fever, chills, cough, sore throat, headache, nausea, vomiting, and pain at the site of exposure.  Serious neurological symptoms usually present themselves two to ten days after the initial symptoms.  There are two types of syndromes that may develop during this neurological period:  furious and/or paralytic (sluggishness and early paralysis).

Rabies is caused by a lyssavirus (a form of virus that causes encephalitis) that affects the saliva and nervous system.  Most cases of rabies in humans are caused by a bite or scratch from an infected animal.  It is possible, but rare, for people to get rabies if infectious material from a rabid animal, such as saliva, gets directly into their eyes, nose, mouth, or a wound.

Rabies in humans has been almost completely eliminated in most developed countries.  The vaccinations of domesticated animals and elimination of stray dogs has helped control this problem.  In the 1980’s the U.S. Centers for Disease Control had one case per year reported.  In the United States rabies is found primarily among wild animals such as skunks, foxes, bats, and raccoons.  There were 49 cases of human rabies reported in the U.S. between 1960 and 1986.  Only 7 of the 49 cases were acquired by exposure to rabid domesticated animals.  The remainder were from wild animals.

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

Cerebral Malaria is a serious complication of falciparum malaria.  This disorder is usually seen in infants, pregnant women, and travelers who are not immune to parasites of certain regions.  It is caused by a communicable parasite and is spread through the bite of the Anopheles mosquito.  The symptoms may be fever of up to 104 F, severe headache, drowsiness, confusion, or delirium.  (For more information on this disorder choose Malaria as your search term in the Rare Disease Database.)

Medical assistance should be obtained as soon as possible after an exposure or possible exposure to rabies. The most effective treatment for rabies is immediate treatment of the wound followed by immunization with the rabies vaccine. The wound should be cleansed thoroughly with soap and water and medical attention sought immediately. If the wound has broken the skin, a tetanus shot should be given. If the patient has been bitten by a wild animal that has escaped, or a domestic animal that shows signs of rabies, a series of vaccinations to prevent rabies is prescribed before the onset of symptoms. Once the disease presents itself in the patient there is no effective treatment to stop the progression.


Rabson-Mendenhall Syndrome

Rabson-Mendenhall syndrome is an extremely rare genetic disorder characterized by severe insulin resistance. Insulin, a hormone produced by the pancreas, regulates blood sugar levels by promoting the movement of glucose (a simple sugar) into cells for energy production or into the liver and fat cells for storage.

The symptoms of Rabson-Mendenhall syndrome vary greatly from person to person. Some individuals may be affected more severely than others. The disorder can potentially cause life-threatening complications during childhood or adolescence. Affected individuals may not have all the symptoms listed below. Affected individuals or parents of affected children should talk to their physicians and medical team about their specific case and associated symptoms.

Rabson-Mendenhall syndrome may be caused by changes (disease-causing variants) of the insulin receptor gene. Insulin receptors are molecular structures on the surfaces of certain target cells that bind with insulin, triggering cellular response. Variants of the insulin receptor gene result in a reduced number or an altered structure of insulin receptors. This results in reduced binding with insulin or abnormalities of the post-receptor pathway, with an impaired response to insulin within targeted cells.

Rabson-Mendenhall syndrome affects males and females in equal numbers. Fewer than 50 patients have been reported in the medical literature. The exact incidence of Rabson-Mendenhall syndrome is unknown. Because rare disorders like Rabson-Mendenhall syndrome often go unrecognized, these disorders are under-diagnosed or misdiagnosed, making it difficult to determine the true frequency of Rabson-Mendenhall syndrome in the general population.

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

Two other disorders, leprechaunism and insulin resistance type A, are also caused by variants in the insulin receptor gene. Some researchers think that these three disorders represent a continuum or spectrum of disease. Rabson-Mendenhall would represent an intermediate form of the disorder.


Radiation Sickness

Acute radiation sickness is characterized by nausea, vomiting, diarrhea, anorexia, headache, malaise and rapid heartbeat (tachycardia). With mild ARS, the discomfort subsides within a few hours or days. However, there are three different types of severe ARS, which can develop as a result of high doses (e.g., an atomic explosion) to small doses (e.g., repeated x-rays over a period of days or weeks):

Harmful sources of ionizing radiation are limited primarily to high-energy x-rays used for diagnosis and therapy, and to radium and related radioactive materials. Present sources of potential radiation include nuclear reactors, cyclotrons, linear accelerators, alternating gradient synchrotons, and sealed cobalt and cesium sources for cancer therapy. Numerous artificial radioactive materials have been produced for use in medicine and industry by neutron activation in reactors.

Radiation sickness can affect males and females in equal numbers.

Diagnosis is typically made based on a history of significant radiation exposure. The time between exposure and vomiting also can give good estimates of exposure levels in a patient.


Ramsay Hunt syndrome

facial nerve palsy due to herpes zoster infection

Ramsay Hunt syndrome is a rare neurological disorder that typically affects adults over 60 years of age. The disorder is characterized by facial weakness or paralysis of the facial nerve (facial palsy) and a rash affecting the ear or mouth. Symptoms are usually on one side of the face (unilateral). Ringing in the ears (tinnitus) and hearing loss may also be present. Ramsay Hunt syndrome is caused by the varicella zoster virus (VZV), the same virus that causes chickenpox in children and shingles (herpes zoster) in adults. In Ramsay Hunt syndrome, previously inactive (dormant) varicella-zoster virus is reactivated and spreads to affect the facial nerve.

The symptoms of Ramsay Hunt syndrome vary from person to person. Affected individuals usually experience paralysis of the facial nerve and a rash affecting the ear. These two symptoms do not always occur at the same time. In most people, only one side of the face is affected.

Ramsay Hunt syndrome is caused by the varicella-zoster virus, which is the same virus that causes chickenpox and shingles. The virus can remain dormant for decades in a person who has had chickenpox as a child. Reactivation of the varicella-zoster virus results in a shingles outbreak and, in cases where the varicella-zoster virus spreads to the facial nerves, develops into Ramsay Hunt syndrome. The reason why the virus reactivates and affects the facial nerve in Ramsay Hunt syndrome is unknown.

According to one estimate, 5 out of every 100,000 people develop Ramsay Hunt syndrome each year in the United States. Ramsay Hunt syndrome affects males and females in equal numbers. Anyone who has previously had chickenpox can potentially develop Ramsay Hunt syndrome. However, most patients are adults over the age of 60. Ramsay Hunt syndrome is extremely rare in children.

Shingles, which results in a painful rash, is caused by the reactivation of the varicella zoster virus which lays dormant in people who have had a prior infection with chickenpox. It can affect nerves all over the body, not specific to just the facial region.

Diagnosis of Ramsay Hunt syndrome can be difficult because the symptoms of the disorder (earache, facial paralysis and the distinctive rash) do not always develop at the same time.


快速发病的儿童肥胖-下丘脑功能障碍-低通气-自主神经失调综合征

Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation

late onset central hypoventilation syndrome with hypothalamic dysfunction

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is an ultra-rare disorder of respiratory control and autonomic nervous system (ANS) regulation, with endocrine system abnormalities. Respiratory control is a function of the ANS that is responsible for changing breathing in response to varied activities of daily living (ex. exercise, sleep, eating) and in response to changes in oxygen and carbon dioxide. The ANS is the portion of the nervous system that controls or regulates many automatic involuntary body functions including breathing, heart rate, blood pressure, temperature regulation, bowel and bladder control, and more. The endocrine system is regulated by the hypothalamus, and through hormones it controls growth, energy and water balance, sexual maturation and fertility as well as response to stress.

Children with ROHHAD are seemingly healthy before the rapid-onset weight gain, making the diagnosis even more challenging to parents and health care personnel. Between 1.5 and 7 years of age, these children begin to manifest abnormalities that will evolve into the features of ROHHAD. Most commonly, the first sign is dramatic (often 20-30 pounds) and rapid (over 3 to 12 months) weight gain without associated abnormal increase in hunger (hyperphagia). This rapid-onset obesity is considered a sign of hypothalamic dysfunction (abnormality of the endocrine system). Other hypothalamic abnormalities may not be detected at the time of the rapid weight gain but will be identified any time from months to years following the rapid-onset obesity. These other hypothalamic/endocrine abnormalities may include inability to maintain normal water balance in the body (leading to abnormally high or low sodium levels), high prolactin levels, low thyroid hormone, growth hormone insufficiency, early or late puberty, and low cortisol among other abnormalities. Children with ROHHAD can have variable timing and number of these symptoms of hypothalamic dysfunction, but all will have some abnormalities, especially increased prolactin. After the rapid weight gain, children with ROHHAD will begin to show breathing abnormalities despite normal lungs. Some children may present with obstructive sleep apnea which means that airflow is intermittently blocked during sleep; they may have snoring and they may have pauses in breathing related to the air flow blockage (obstructive apnea). Because obstructive sleep apnea is not unusual in young obese children, health care personnel may not be alarmed at this stage, and a connection to the ROHHAD phenotype might be delayed. All children with ROHHAD, whether they had preceding OSA or not, develop alveolar hypoventilation with very shallow breathing during sleep (nap and night). In more severely affected patients with ROHHAD, the hypoventilation is apparent awake and asleep. As a result of altered control of breathing, low oxygen saturation and elevated carbon dioxide occur during wakefulness as well as sleep, without any shortness of breath (awake) or awakening (from sleep). This hypoventilation/control of breathing deficit is the most life-threatening feature of ROHHAD, yet it is often unnoticed until after a dramatic event such as a cardiorespiratory arrest. Therefore, all children with ROHHAD will require help with their breathing, relying on a ventilator to prevent low oxygen or increased carbon dioxide. Approximately half of the children with ROHHAD require ventilator support during sleep only and the other half require ventilator support awake and asleep (24-hours per day), though the ventilatory needs of a child with ROHHAD may vary with advancing age (and unfolding of the clinical features of ROHHAD). This ventilator support can be provided with bi-level positive airway pressure through a mask that fits tightly at the nose or with nasal pillows or a full-face mask or with a mechanical ventilator through a surgically made hole in the airway called a tracheostomy, or potentially with diaphragm pacing (still requiring a tracheostomy).

The diagnosis of ROHHAD is currently based on clinical criteria and though investigation of genetic changes (pathogenic variants or mutations) is underway, no specific cause for ROHHAD has been found to date.

ROHHAD is a very rare disorder with approximately 200 cases reported in the literature and clinically to date. Though first described under a different name in 1965, it was not re-named until 2007 nor shown to be distinct from CCHS (documented absence of CCHS-related PHOX2B mutations). Therefore, as ROHHAD is a relatively new disorder without many cases identified thus far, it is not yet clear if any certain population is at greater risk for developing ROHHAD. Because of the explosion of children with exogenous obesity worldwide, a very high level of vigilance in consideration of ROHHAD is essential.

Congenital central hypoventilation syndrome (CCHS) is a disorder of the ANS caused by a harmful variant in the PHOX2B gene that affects the embryologic development of the ANS. Similar to ROHHAD, the automatic control of breathing, heartbeat, digestion, and other features of ANSD are among the affected features. In CCHS, the hallmark is hypoventilation while sleeping and, in severe cases, hypoventilation while awake and asleep – despite anatomically normal heart, lung, and airways. Both CCHS and ROHHAD fall within the rubric of respiratory and autonomic disorders of infancy, childhood, and adulthood (RADICA). CCHS is a rare disorder with approximately 3,000 cases described or identified worldwide. Numbers of reported CCHS cases continue to grow, likely because of increased awareness and introduction of a clinically available genetic test (in 2003) – allowing for early diagnosis and improved treatment. CCHS is often diagnosed in the newborn period because of the hypoventilation and related cyanosis  upon falling asleep and/or associated Hirschsprung disease, but milder forms of CCHS may go undiagnosed through infancy, childhood, and even adulthood. A simple blood test can be done to look for a PHOX2B gene variant. Different PHOX2B gene variants can occur, and this will determine how severely an individual with CCHS is affected. Stepwise testing for PHOX2B variants should be done with close involvement by a physician and genetic counselor. (For more information about this disease, choose CCHS as your search term in the Rare Disease Database.)

The criteria for diagnosis of ROHHAD include the following: 1) rapid-onset obesity and alveolar hypoventilation during sleep starting after the age of 1.5 years, 2) evidence of hypothalamic dysfunction, as defined by at least 1 of the following findings: rapid-onset obesity, hyperprolactinemia, central hypothyroidism, disordered water balance, growth hormone deficiency, corticotrophin deficiency, or altered onset of puberty (delayed or precocious), and 3) absence of a CCHS-related PHOX2B variant (to genetically distinguish ROHHAD from CCHS). At present there is no genetic testing available to diagnose ROHHAD, so the diagnosis is based on the clinical presentation and clinical course which should include cooperative consultation by pediatric experts in the fields of pulmonology, endocrinology, autonomic medicine, oncology, psychology, nutrition, otolaryngology, surgery, cardiology and sleep medicine.


Rasmussen Encephalitis

Rasmussen encephalitis, sometimes referred to as Rasmussen syndrome, is a rare disorder of the central nervous system characterized by chronic progressive inflammation (encephalitis) of one cerebral hemisphere. As a result, the patient usually experiences frequent episodes of uncontrolled electrical disturbances in the brain that cause epileptic seizures (epilepsy) and progressive cerebral destruction. With time, further symptoms may include progressive weakness of one side of the body (hemiparesis), language problems (if on the left side of the brain) and intellectual disabilities. The exact cause of this disorder is not known. The two leading ideas are that the brain inflammation might be a reaction of a foreign antigen (infection) or an autoimmune disease limited to one side of the brain resulting in brain damage. It occurs mostly, but not always, in children between the ages of two and ten years, and in many patients the course of the disease is most severe during the first 8 to 12 months. After the peak inflammatory response is reached, the progression of this disorder appears to slow or stop, and the patient is left with permanent neurological deficits.

Typically, affected individuals develop focal seizures that may progress to near continuous seizures termed epilepsia partialis continua (EPC). EPC is characterized by a rapid, rhythmic succession of contractions and relaxations of a muscle or muscle group (myoclonus), particularly of the arms, legs, and face, that may occur singularly or in a repetitive, continuous series. In Rasmussen this occurs consistently on one side of the body opposite the side of the inflammation.

The exact cause of Rasmussen encephalitis is not known. Most researchers now suspect that Rasmussen encephalitis is an autoimmune disorder following histopathologic review of the tissue involved under the microscope. In autoimmune disorders, the body’s natural defenses (antibodies and T-cells) fight its own tissue, mistaking it for foreign organisms for no apparent reason.

Rasmussen encephalitis mostly affects children ten years of age and younger. It is unusual to affect children under two years of age. Adolescents and young adults in much smaller proportions are also affected. There may be a history of some prior mild cold or flu prior to the onset of the seizures. The annual number of new-onset Rasmussen has been estimated as 2.4/10,000,000 persons less than or equal to 18 years of age.

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

Focal cortical dysplasia in the motor region refers to lesions near the motor-sensory cortex that can provoke EPC which is similar to RE.


Reactive arthritis

Reactive arthritis is a general term for a form of joint inflammation (arthritis) that develops as a reaction to an infection in another area of the body (i.e., outside of the joints). Joint inflammation is characterized by redness, swelling, pain and warmth in and around the affected joint. In reactive arthritis, the large joints of the lower limbs and the sacroiliac joints are most often affected. Two other common symptoms of reactive arthritis are inflammation of the urinary tract and inflammation of the membrane (conjunctiva) that lines the eyelids (conjunctivitis). These three characteristic symptoms may occur separately, all at once or not at all. Additional symptoms such as fever, weight loss, lower back pain and heel pain may also occur. Reactive arthritis usually develops following a bout with certain bacterial infections including Chlamydia, Salmonella, Shigella, Yersinia, and Campylobacter.

Some individuals with reactive arthritis may only develop mild arthritis without eye or urinary tract involvement. Other individuals may develop a severe case of reactive arthritis that can dramatically limit daily activity. Symptoms usually last anywhere from 3 to 12 months and may come and go. In approximately 30-50 percent of patients, symptoms may return later or become a chronic (greater than 6 month) long-term problem. It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis. The specific symptoms and their severity can vary greatly from one person to another.

Reactive arthritis develops because of an infection that occurs in another part of the body. Even mild infections, which may go unnoticed, can cause reactive arthritis. This may be particularly true with chlamydial infections, which appear to be a rather frequent cause of reactive arthritis. The lack of a symptomatic, preceding infection in some cases obscures the diagnosis. The five bacterial infections most commonly associated with reactive arthritis are Chlamydia, Salmonella, Shigella, Yersinia, and Campylobacter. These bacteria usually cause gastrointestinal or genitourinary infections. Chlamydia is the most common cause of reactive arthritis in the United States and is usually acquired through sexual contact. Salmonella, Shigella, Yersinia, and Campylobacter may cause a gastrointestinal infection that can trigger reactive arthritis. Salmonella, Shigella, Yersinia, and Campylobacter are often acquired after eating contaminated food, handling improperly prepared food or coming into contact with the feces of a contaminated person. Less often, several other bacteria have been implicated as causative agents in reactive arthritis. However, some researchers reserve the term reactive arthritis only for those cases caused by the five abovementioned bacteria.

Reactive arthritis most often affects white men between the ages of 20 and 40. However, it has also been reported in children and the elderly. Women usually develop milder symptoms and may often go undiagnosed. Men are estimated to be approximately nine times more likely to develop reactive arthritis following a sexually-acquired infection. The risk of developing reactive arthritis following a gastrointestinal infection is the same between men and women. The exact incidence of reactive arthritis is unknown and estimates vary. Some researchers believe that many cases often go misdiagnosed or undiagnosed.

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

There is no specific, conclusive diagnostic test for reactive arthritis. Several groups have published diagnostic guidelines for reactive arthritis. However, these guidelines are often in disagreement as to what specifically is required for a diagnosis. Specific, consistent diagnostic guidelines have yet to be established for reactive arthritis.


Multiple epiphyseal dysplasia type 4

The specific symptoms and physical findings may vary from one person to another. Affected individuals may develop relatively mild symptoms and, in some cases, individuals reach adulthood without ever receiving a diagnosis of recessive multiple epiphyseal dysplasia. However, most individuals are diagnosed with a skeletal dysplasia at some point during childhood. Other individuals may have more severe complications.

Recessive multiple epiphyseal dysplasia is caused by a mutation in the SLC26A2 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.

Recessive multiple epiphyseal dysplasia affects males and females in equal numbers. The exact incidence or prevalence of the disorder is unknown, but multiple epiphyseal dysplasia, collectively, has been estimated to occur in approximately 1 in 20,000 people in the general population. rMED is estimated to account for approximately 25% of all cases of multiple epiphyseal dysplasia. Because some cases go undiagnosed or misdiagnosed, determining the true frequency these disorders in the general population is difficult.

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

A diagnosis of recessive multiple epiphyseal dysplasia is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. The disorder may be suspected in individuals with joint pain, particularly in the hips and knees, skeletal malformation of the hands, feet and knees, and scoliosis.


Recurrent Pericarditis

The main symptom of pericarditis is chest pain, which is present in the vast majority of affected individuals. Typically, the pain is described as sharp and worse when coughing or taking a deep breath (pleuritic). The typical pain seen in pericarditis is also worse when lying down and is partially relieved when leaning forward. It can radiate to the neck, upper back or shoulders. Other symptoms that are associated with pericarditis include shortness of breath (dyspnea), fever, fatigue, malaise and the sensation of an irregular heartbeat (palpitations). Another feature frequently seen in pericarditis is accumulation of fluid in the space between the heart and the pericardium (pericardial sac), which is known as a pericardial effusion. The symptoms seen with a second or subsequent episode of recurrent pericarditis are often similar to the first event, although they tend to be less severe with recurrences. An episode of pericarditis can last days to weeks or longer. Although the symptoms of pericarditis can significantly affect quality of life, affected individuals typically have no symptoms between episodes. The number of episodes of recurrent pericarditis varies greatly between patients.

The causes of pericarditis can be divided in two major categories: those that lead to isolated pericarditis and systemic diseases that can involve the pericardium as one of their manifestations. Most cases of isolated pericarditis are idiopathic. Viral infections have been considered to initiate first episodes of idiopathic pericarditis, but it is not clear how often this is actually the case. Dysfunction of the immune system is thought to play a role in recurrent cases of idiopathic pericarditis. Bacteria (notably tuberculosis), parasites and fungi can also be implicated more rarely, but it is unusual for these non-viral infections to be limited to the pericardium. Pericarditis can also occur after a heart attack (peri-infarction pericarditis and Dressler syndrome) or after cardiac surgery (post-pericardiotomy syndrome) and other types of invasive cardiac procedures. These types of pericarditis are known collectively as post-cardiac injury pericarditis.

Pericarditis is estimated to affect about 28 individuals per 100,000 in the general population every year. Apart from individuals with predisposing conditions, the most frequently affected group are men between the ages of 20 and 50. However, the disease can occur in people of any demographic, including children. It is estimated that about 15 to 30% of individuals that have an initial episode of idiopathic pericarditis will develop recurrent pericarditis.

Symptoms of the following disorders can resemble or be confused with those of pericarditis.

The diagnostic evaluation of a patient with suspected pericarditis begins with a complete patient history and physical examination in order to evaluate risk factors, signs and symptoms of the disease, and features that could suggest an alternative diagnosis. An essential part of the physical examination is auscultation of the heart using a stethoscope; in some patients, a characteristic scratching sound, known as a pericardial friction rub, may be heard. The physical exam can also show signs of cardiac tamponade or constrictive pericarditis, such as dyspnea, distended neck veins, edema, or low blood pressure.

In every patient with pericarditis, restriction of physical activity is recommended until symptoms have resolved and inflammatory markers have normalized. If a systemic disease is identified as the cause of pericarditis, therapy should be focused on treating the underlying condition. For instance, antibiotics will be required for a patient with tuberculosis, and chemotherapy or other treatments will be required in a patient with neoplastic pericarditis. Another important consideration is whether the affected individual needs to be admitted to the hospital or can be treated as an outpatient. Although most patients can be treated outside the hospital, patients with high-risk features are usually admitted. These features include fever, a slow (subacute) onset of disease without sudden onset of chest pain, presence of a large pericardial effusion, use of immunosuppressant medications or blood thinners (anticoagulants) or high troponin levels (which suggests myopericarditis).


Recurrent Respiratory Papillomatosis

The specific symptoms, course of the disease, and severity of RRP can vary greatly from one person to another. In some people, the disease may resolve without treatment (spontaneous remissions) or it may remain stable requiring only periodic intervention (e.g. only a few surgeries during their lifetime). In other peoople, the disease may be aggressive requiring frequent medical intervention and potentially more than 100 surgeries during a person’s lifetime.

Recurrent respiratory papillomatosis is caused by the human papillomavirus (HPV). This virus is common in human beings with some studies estimating that as many as 75%-80% of men and women will be affected by HPV at some point during their lives if they are not vaccinated against the virus. HPV is passed through genital contact, most often during sex. Most individuals who are infected with HPV never develop any symptoms. There are more than 150 different subtypes of HPV and approximately 40 of these subtypes can affect the genital tract. Two specific subtypes, HPV 6 and HPV 11, account for more than 90% of cases of RRP. These two subtypes are the same HPV subtypes most often identified in genital warts (anogenital condyloma). HPV subtypes 16 and 18 account for most of the remaining cases. Together, these four subtypes are responsible for about 70% of cases of cervical cancer.

The juvenile form of recurrent respiratory papillomatosis affects males and females in equal numbers. The adult form affects males slightly more often than females. In the United States, the incidence of RRP was previously estimated to be approximately 2 per 100,000 adults and 4 per 100,000 children with approximately 1,000 new pediatric cases in the United States each year. With the increased uptake of the HPV vaccine, these numbers are dropping precipitously. In children, JORRP is most often diagnosed between the ages of 2-4. In adults, the disorder occurs most often in the third or fourth decade though a second peak around age 60 has recently been noted.

A variety of conditions can produce signs and symptoms that are similar to those seen in RRP. Such conditions include asthma, allergies, chronic bronchitis, croup, vocal nodules and gastroesophageal reflux. Comparisons may be useful for a differential diagnosis.


Refractory celiac disease

Refractory celiac disease (RCD) is a complex autoimmune disorder much like the more common celiac disease but, unlike celiac disease, it is resistant or unresponsive to at least 12 months of treatment with a strict gluten-free diet. Gliadin, a component of the wheat storage protein gluten, together with similar proteins in barley and rye, are the villains that trigger the immune reaction in celiac disease. The diagnosis of RCD is made by exclusion, especially of any other disorder that can affect the huge number of thread-like projections that line the interior of the intestine (intestinal villi), such as intestinal lymphoma, Crohn’s disease, small intestinal bacterial overgrowth or hypogammaglobulinemia.

The symptoms of refractory disease are not unlike those of untreated celiac disease except that they are usually more severe and more disabling. The more common symptoms include weight loss, diarrhea, abdominal pain, malnutrition and anemia.

The exact series of events that leads to refractory celiac disease remains unresolved. Involved are the body’s immune system, especially T lymphocytes and intraepithelial lymphocytes (IEL), cytokines, and antigens. Lymphocytes make up about 25% of a person’s white blood cells and include the B-cells (mature in bone marrow) and T-cells (mature in the thymus), each of which play key roles in the development of immunity. Intraepithelial lymphocytes (IELs) are T-cells that exist in the lining (intraepithelial) of the intestine. A protein on the surface of T lymphocytes called the T-cell receptor (TCR) serves as a docking bay for specific antigens. In celiac disease, T-cells that recognize gluten proteins are activated and proliferate. When gluten is removed from the diet, these T-cells become inactive and the intestinal damage heals. In refractory celiac disease, intestinal T cells are activated without gluten stimulation and intestinal injury persists despite the removal of dietary gluten.

Refractory celiac disease is rare among adults and is almost never seen in children. Data regarding the true incidence and prevalence of RCD are unreliable, but some have estimated that there might be 20,000 patients in the USA. However, those estimations are based on incomplete data. In one recent study, 1.5% of patients diagnosed with celiac disease at a single US center developed RCD. Of those with RCD 85% had the less severe Type I RCD.

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

Virtually all clinicians studying refractory celiac disease emphasize that the diagnosis is based on eliminating all other possible sources of the symptoms and intestinal injury. One article lists more than 10 conditions that must be considered and eliminated before a convincing diagnosis of refractory celiac disease may be made. As noted above, examination of the interior wall of the intestine (upper and lower) by means of an enteroscope or colonoscope as well as obtaining intestinal biopsies to be examined under a microscope is useful, especially to determine if the symptoms are the result of intestinal disorders other than RCD. Capsule endoscopy, which examines the small intestinal lining using a camera mounted on a swallowed pill, may also be useful in evaluating the degree of small intestinal inflammation and injury.  Some specialized centers are able to offer sophisticated examinations of the biopsy materials that in many cases will assist in the diagnosis. These studies emphasize the presence of abnormal populations of T lymphocytes in the tissue indicating a diagnosis of the more aggressive Type II RCD. Other imaging studies (barium X-ray, CT scan, capsule enteroscopy and MRE) may be undertaken, especially if there is concern for the presence of a lymphoma.

Several therapies for RCD have been tried in uncontrolled tests with inconclusive results. Among the therapies tested in this way are: elemental diet (an elemental diet is a liquid diet consisting of nutrients that require no digestion, including amino acids, carbohydrates, vitamins, minerals, and triglycerides); and total parental nutrition (TPN) that is defined as nutrition maintained entirely by intravenous injection or by some other nongastrointestinal route. Steroid therapy is a mainstay of treatment but its beneficial effect is short-lived in patients of lymphoma. Treatment involving other immunosuppressive drugs such as azathioprine, cyclosporine, enteric-coated budesonide, 5-aminosalicylic acid (5-ASA), or inflixamab has been used with a limited number of patients.  More recently chemotherapy with cladribine with or without autologous stem cell transplantation has also been reported to be useful.


Refsum disease

disorder of cornification 11 (phytanic acid type)

At birth, individuals with Refsum disease generally appear normal although they may show shorter bones in the hands and feet (metacarpals and metatarsals, respectively). Between 10 and 20 years old, individuals may show their first symptom which is most frequently the loss of night vision (retinitis pigmentosa). Some people may not show any symptoms until up to 50 years of age. Retinitis pigmentosa occurs because light-sensing cells in the retina, a layer in the back of the eye, gradually deteriorate. The initial loss of night vision usually occurs during childhood, and the progression toward loss of peripheral vision and full blindness may occur over the course of years.

Most cases (90%) of Refsum disease result from a change (mutation) in the PHYH gene. Most of the remaining cases result from a mutation in the PEX7 gene which transports PHYH into the peroxisomal compartment in cells.  Mutations in PHYH and PEX7 genes cause abnormal functioning of peroxisomes, which are structures that allow for the breakdown of fatty acids, including phytanic acid. Specifically, PHYH codes for the phytanoyl-CoA hydroxylase enzyme that is used in the peroxisome to break down phytanic acid. Phytanic acid comes from the diet and is derived from bacterial fermentation of green plants or algae. It is commonly found in dairy, beef, lamb and other ruminant animal-derived food stuffs as well as some seafood. The improper functioning of the peroxisome and related enzymes means that phytanic acid cannot be broken down and thus accumulates in the cell. It is currently unclear how the buildup of phytanic acid is toxic and affects vision or how it causes other features of the disease.

Refsum disease occurs in approximately 1 in 1,000,000 people. Males and females are affected in equal numbers.

Phytanic acid levels can also be raised in other disorders.

Refsum disease can be diagnosed based on the finding of highly raised phytanic acid in a blood sample. Levels of pristanic acid, the next step in the pathway, are usually low.  This initial diagnosis must then be confirmed with either molecular genetic testing for mutations in either the PHYH or PEX7 genes or by enzyme analysis in a skin biopsy to determine if there is abnormal activity of the enzyme phytanoyl-CoA hydroxylase pathway.


Relapsing polychondritis

Relapsing polychondritis is a rare degenerative disease characterized by recurrent inflammation of the cartilage in the body. Deterioration of the cartilage may affect any site of the body where cartilage is present. Ears, larynx and trachea may become floppy, and the bridge of the nose can collapse into a saddlenose shape. The aortic heart valve may also be affected.

Symptoms of relapsing polychondritis usually begin with the sudden onset of pain, tenderness and swelling of the cartilage of one or both ears. This inflammation may spread to the fleshy portion of the outer ear causing it to narrow. Attacks may last several days to weeks before subsiding. Middle ear inflammation can cause obstruction of the eustachian tube. Recurrent attacks may lead to hearing loss.

The exact cause of relapsing polychondritis is not known. It is thought to be an autoimmune disease. Autoimmune disorders are caused when the body’s natural defenses against foreign or invading organisms (e.g., antibodies) begin to attack healthy tissue for unknown reasons. Some cases may be linked to abnormal reactions by blood cells (serum antibodies), to a thyroid protein (thyroglobulin), organ wall (parietal) cells, adrenal cells, or thyroid. Symptoms of relapsing polychondritis may arise when autoantibodies attack human cartilage.

Relapsing polychondritis affects males and females in equal numbers. Symptoms usually begin between forty and sixty years of age.

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

Rheumatoid arthritis is a disease of unknown origin which may have a relationship to autoimmune processes. This disorder is characterized by lack of appetite (anorexia), tiredness, painful and deformed joints, early morning stiffness chiefly in the hands, knees, feet, jaw, and spine. Once affected, a patient’s joints remain painful or uncomfortable for weeks, months, or even years.


Renal Agenesis, Bilateral

Bilateral Renal Agenesis is the absence of both kidneys at birth.  It is a genetic disorder characterized by a failure of the kidneys to develop in a fetus. This absence of kidneys causes a deficiency of amniotic fluid (Oligohydramnios) in a pregnant woman. Normally, the amniotic fluid acts as a cushion for the developing fetus. When there is an insufficient amount of this fluid, compression of the fetus may occur resulting in further malformations of the baby.

Bilateral renal agenesis is characterized by the absence of kidneys and of urine in a baby.  The face usually consists of wide-set eyes; a parrot beak nose; a receding chin, and large low set ears deficient in cartilage.  Other symptoms may include excess and dehydrated skin, a prominent fold at the corner of each eye, the facial expression of an older infant, and deformities of the hands and feet.

Bilateral renal agenesis is an autosomal dominant genetic disorder.  Human  traits, including the classic genetic diseases, are the product of the  interaction of two genes, one received from the father and one from the  mother.  In dominant disorders, a single copy of the disease gene (received  from either the mother or father) will be expressed dominating the other  normal gene and resulting in the appearance of the disease.  The risk of  transmitting the disorder from affected parent to offspring is 50 percent for  each pregnancy regardless of the sex of the resulting child.

Bilateral renal agenesis is found in male infants more frequently than females.  It tends to occur in the children of parents having kidney abnormalities.  It is a very rare disorder.

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

Oligohydramnios Sequence (Potter Syndrome) is characterized by an insufficient level of amniotic fluid.  It may be caused by the absence of urinary output by the fetus or by chronic leakage of fluid from the amniotic sack.

Treatment of bilateral renal agenesis is symptomatic and supportive.


Renal Cell Carcinoma

Renal cell carcinoma is a form of kidney cancer. Some patients with renal cell carcinoma do not have symptoms (asymptomatic). When symptoms are present, they may include blood in the urine; urine that is brown or rusty-colored; abdominal pain; weight loss; enlargement of one testicle or varicose veins of the testis (varicocele) in a male patient; fever; a thin, malnourished appearance; vision abnormalities; and elevated blood pressure. The most common feature of the syndrome is the passing of blood in the urine (hematuria).

Renal cell carcinoma, though rare, is the most common form of kidney cancer found in adults.  Usually the first sign that something is wrong is the passing of blood in the urine.   Other signs may include flank pain and an abdominal mass that can be felt by the examining doctor.  Other symptoms of renal cell carcinoma may include high blood pressure (hypertension), anemia, abnormal liver function and fever.  Sometimes symptoms do not appear until the cancer has spread to another part of the body, usually the lymph nodes, lungs or the long bones.

The exact cause of renal cell carcinoma is not known.  However, a history of smoking does increase the risk for developing this disease.  Patients with von Hippel-Lindau disease, horseshoe kidneys, adult polycystic kidney disease and kidney failure are also more prone to develop renal cell carcinoma.

Renal cell carcinoma is more common in males than in females (ratio of 2 or 3 to 1) and in persons with a history of smoking.  It is also more common in persons with other types of kidney disorders and tends to run in some families.  Renal cell carcinoma accounts for approximately 30,000 new cases of kidney malignancies per year in the United States.

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

Benign familial hematuria is a nonprogressive kidney disorder that usually begins in childhood and is characterized by red blood cells in the urine, and thinning of the microscopic parts of the kidney.  It is often preceded by a respiratory infection.  (For more information on this disorder, choose Hematuria as your search term in the Rare Disease Database.)


Renal Glycosuria

Renal (kidney) glycosuria is a rare condition in which too much of the simple sugar glucose is removed through the urine. This happens even though there are normal or low levels of glucose in the blood. When the kidney is working correctly, glucose is only removed into the urine when there is too much in the blood. However, in people with renal glycosuria, glucose is removed in the urine when it should not be because the renal tubules in the kidneys are not working properly. The renal tubules are the part of the kidney that cleans the blood. Most affected people have no symptoms (asymptomatic). When renal glycosuria occurs by itself, the condition can be inherited in an autosomal dominant or autosomal recessive pattern.

In people with renal glycosuria, glucose is removed in the urine even though there are normal or low levels of glucose in the blood. As blood flows through the kidneys, glucose and other substances are cleaned from the liquid portion of the blood. The newly cleaned blood then moves through tubes in the kidneys (renal tubules). Helpful substances, including glucose, sodium, and wate, are reabsorbed and returned to the bloodstream. Unwanted substances are removed from the bloodstream through the urine. When the kidney is working, glucose is only removed into the urine when there is too much sugar in the blood. However, in people with renal glycosuria, extra glucose is removed and/or, the kidney is unable to reabsorb glucose as quickly as it should. (For more, see Causes below.)

Renal glycosuria is an inherited problem of membrane transport (i.e., an abnormal renal transport syndrome). Membrane transport disorders are marked by problems with the movement (i.e., transport) of one or more compounds across the outer layer of the cell (cell membranes). They are thought to result from harmful genetic changes (mutations) that cause certain membrane proteins to not be made correctly.

Renal glycosuria occurs in about 1/33,000 people in the general population and affects males and females equally. Most people with renal glycosuria have no symptoms (asymptomatic). Less commonly, serious symptoms (e.g., dehydration, ketosis) may be seen. This happens most often under certain conditions such as pregnancy or starvation.

Certain features of the following disorders may be similar to those connected to renal glycosuria. Comparisons may be useful for a making a correct diagnosis:

Diabetes mellitus is a common disorder of high blood sugar (glucose) levels. It is due to a lack of insulin or an inability to use insulin. The hormone insulin helps with movement of glucose into cells for the body’s energy needs. Insulin may also go into liver and fat cells for storage. Too little insulin may lead to poor absorption of glucose leading to increased levels of glucose in the blood (hyperglycemia) and high levels of glucose in the urine (glycosuria). Not enough insulin may lead to reduced breakdown of fat (fat metabolism) and degeneration or loss of function of certain blood vessels. Symptoms may include excessive urination (polyuria) and increased thirst (polydipsia), and excessive hunger and eating (polyphagia). Other complications may arise without proper treatment. Although the exact causes of diabetes mellitus are not known, genetic factors are thought to play some role.


Renal Medullary Carcinoma

The most common first sign of RMC is blood in the urine (hematuria) and patients may also feel pain in their flank around the kidney area or (less commonly) feel a mass in their abdomen, usually on the right side. About half of the patients with RMC will begin losing weight unintentionally and may develop fevers and night sweats.

The exact reason why RMC develops is not fully understood but almost all patients have a blood disorder that can make their red blood cells sickle. These disorders are called sickle hemoglobinopathies and include sickle cell trait and sickle cell disease. Of note, most individuals with sickle cell trait are otherwise healthy and many are not aware that they have this blood disorder. Other than the presence of sickle hemoglobinopathy, there are no other known genetic predispositions that can explain why only certain individuals will develop RMC. There is currently no evidence to suggest that family members of a patient with RMC are at increased risk for developing RMC themselves. Although individuals with sickle hemoglobinopathies should take early signs and symptoms of possible RMC very seriously, there are currently no known effective strategies to screen for RMC in individuals without symptoms.

RMC predominantly afflicts young adults and adolescents with sickle cell trait, sickle cell disease or other hemoglobinopathies that can cause red blood cells to change into a sickle shape. In the United States, such sickle hemoglobinopathies are mainly found in individuals of African descent. In other countries such as Greece, sickle hemoglobinopathies are found mainly in Caucasians. The presence of these sickle hemoglobinopathies increases the risk of RMC regardless of race or ethnicity. Men are twice as likely to be affected by RMC than women, and about 70% of RMC cases start from the right kidney. RMC is the third most common kidney cancer among children and young adults. Half of the patients diagnosed with RMC are 28 years old or younger with some being as young as 9 years old. Less commonly, patients can be 35 years old or older.

Young children (average age of 9 years old) with sickle cell trait are also at risk for developing another distinct cancer named VCL-ALK renal cell carcinoma (VCL-ALK RCC) also arising from the renal medulla. This cancer is characterized by the fusion of two genes called VCL and ALK. This VCL-ALK fusion is not found in RMC. Furthermore, VCL-ALK RCC expresses INI1 and is generally a much less aggressive cancer than RMC.

Because RMC does not cause symptoms early in the disease, getting an early diagnosis is difficult. Since treatment of RMC can be more effective the earlier the disease is identified, early diagnosis is important.


Infant acute respiratory distress syndrome

Infant respiratory distress syndrome is a lung disorder that tends to affect premature infants. Major symptoms include difficulty in breathing and collapsed lungs, potentially requiring mechanical ventilation or positive end-expiratory pressure (PEEP).

Infant  respiratory  distress syndrome is characterized by diminished oxygen intake in the premature newborn. A clear membrane is found lining the alveolar (air cell) ducts in the lungs and is associated with reduced amounts of lung wetting agents or emulsifier (surfactant).  The surfactant is a lipoprotein based on lecithin that stabilizes alveolar membranes.  When this surfactant is missing, breathing is difficult and may lead to collapse of a lung.  The affected infant must be placed on some type of ventilation, either mechanical or physical, in order to continue breathing.

Infant respiratory distress syndrome is caused by the absence of a natural lung wetting agent (surfactant) in the immature lungs of infants.  Since surfactant normally develops late in prenatal life it usually is not present in the very premature infant of about 26-36 weeks of gestational age.  This can result in improper functioning of the alveoli (air cells) of the lungs causing breathing difficulties and collapsed lungs.

Infant respiratory distress syndrome affects male and female premature infants in equal numbers.  Among approximately 250,000 infants born prematurely each year in the United States, up to 50,000 will have IRDS which will kill approximately 5,000 of them.  Due in large part to the use of surfactants beginning in 1989, infant mortality rates in the United States have dropped from 9.7 per 1,000 births in 1989 to 8.9 per 1,000 births in 1991.  Infants with surfactant protein-B deficiency do not respond to surfactant replacement therapy.

Symptoms of the following disorders can be similar to those of infant respiratory distress syndrome, although they tend to affect older children or adults:

Treatment of infant respiratory distress syndrome consists of mechanical or physical breathing assistance such as positive end expiratory pressure (PEEP). Other treatment is symptomatic and supportive.


视网膜血管病变伴脑白质营养不良和全身表现

Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations

Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations

Hallmark symptoms of RVCL-S usually begin in middle age (~35-50 years) with eye issues such as an increasing number of floaters and blind spots. The main pathologic process of RVCL-S is that small blood vessels prematurely drop out; that is, deteriorate and disappear [3]. This leads to mini strokes (or micro-infarcts) in tissues. The loss of blood supply affects both the eye (retina) and the brain (white matter) since these organs serve key functions and are sensitive to even small disruptions in blood flow. As more vessels drop out, there is development of increased vision loss and larger brain infarcts (or tumor-like lesions), especially if the mini-strokes are clustered.

A mutation in the TREX1 gene causes RVCL-S. The abnormal gene results in production of a truncated form of TREX1 protein.

RVCL-S affects males and females with equivalent frequency and commonly begins in middle age (35-50 years). It is commonly first noticed as eye symptoms (increased ‘floaters’ or ‘blind spots’). Patients have been identified in several countries including the USA, UK, Australia, China, France, Germany, Italy, Japan, Mexico, the Netherlands, Spain, Switzerland, Taiwan and Turkey.

RVCL-S is frequently misdiagnosed. This may lead to unnecessary and invasive diagnostic procedures such as biopsies of brain, liver or kidney. Symptoms of the following disorders can be similar to those of RVCL-S:

RVCL-S should be considered when a middle-aged individual has retinal and microvascular abnormalities, in addition to a family history of similar symptoms. The definitive work up is genetic testing for mutations in the TREX1 gene from a small blood sample. Mutations on just one allele, in a specific region distal to the enzyme region, conclusively establish if the patient has the disease. Additional testing may include a retinal exam and a brain MRI. Genetic counseling, as well as consultation with a physician familiar with RVCL, is strongly recommended prior to genetic testing.


Retinitis Pigmentosa

Retinitis pigmentosa (RP) comprises a large group of inherited vision disorders that cause progressive degeneration of the retina (the so-called inherited retinal diseases, or IRDs), the light sensitive membrane that coats the inside of the eyes. Peripheral (or side) vision gradually decreases and eventually is lost in most patients. Central vision is usually preserved until late in these conditions. Some forms of RP can be associated with deafness, obesity, kidney disease and various other general health problems, including central nervous system and metabolic disorders and occasionally chromosomal abnormalities.

RP usually begins as night or dim light visual impairment (that is, difficulty seeing in dimly lit environments or at dusk, or adapting to, or recovering function in, dim light after being in bright light for any length of time). Typically, this is followed by the affected individual’s growing awareness of a loss of peripheral vision. Symptoms are more often noticed between the age 10 and 40, but earlier and later onset forms of RP exist. Characteristically, symptoms develop gradually over time. The sudden onset of these same symptoms should point to a different cause, such as an autoimmune process. Older people with sudden onset of these symptoms are especially at risk for experiencing them as the result of having cancer (so called paraneoplastic retinopathy, which often co-occurs with an optic nerve involvement as well).

Retinitis pigmentosa is a group of hereditary progressive disorders that may be inherited in an autosomal recessive, autosomal dominant or X-linked recessive pattern. Maternally inherited variants of RP transmitted via the mitochondrial DNA also exist.

RP as a group of vision disorders affects about 1 in 3,000 to 1 in 4,000 people in the world. This means that, with a population of about 330 million in the United States in February 2021 (see https://www.census.gov for continuous updates), about 82,500 to 110,000 people in the United States have RP or a related disorder. With a worldwide population presently estimated at over 7.74 billion, it can be estimated that approximately 1.94 to 2.58 million people around the world have one of these disorders. Excluding age-related macular degeneration and glaucoma, the genetic causes of which are complex and linked simultaneously to more than one gene (so called polygenic disorders), RP is the most common cause of inherited visual loss.

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

Leber congenital amaurosis (LCA), severe early childhood-onset retinal dystrophy (SECORD), and early-onset RP (EORP) are special forms of RP characterized by the presence of severe symptoms from birth or shortly thereafter, respectively. This sub-group of RP forms is inherited in an autosomal recessive fashion, although X-linked RP also tends to have a significantly earlier onset than other forms of RP. When present from birth as in LCA, the visual deficit of affected children is typically recognized because of the coexistence of unsteadiness of the eyes known as nystagmus. Nystagmus is characterized by either fast-beating movements or by wandering movements of the eyeballs. The appearance of the back of the eye can be normal or near normal for several years, but testing of retinal function in response to flashes of light (the electroretinogram, or ERG) will invariably reveal the disease status in these patients. LCA patients often develop a deformation of the cornea causing high astigmatism up to a frank cone-shaped deformation of the cornea known as keratoconus. Prompt recognition of, and molecular genetic diagnostic testing for LCA has become increasingly important, since an FDA-approved gene therapy called Luxturna has become commercially available in 2017 as a treatment for one form of LCA linked to the RPE65 gene (see below). There are many different genes responsible for LCA and for recessive EORP. (For more information on this condition, choose Leber congenital amaurosis as your search term in the Rare Disease Database)


Retinoblastoma

Retinoblastoma is an extremely rare malignant tumor that develops in the nerve-rich layers that line the back of the eyes (retina). The retina is a thin layer of nerve cells that senses light and converts it into nerve signals, which are then relayed to the brain through the optic nerve. Retinoblastoma is most commonly diagnosed in children under the age of three. The most typical finding associated with retinoblastoma is the reflection of light off a tumor behind the lens of the eye, which causes the pupil to appear white, the so-called cat’s eye reflex (leukocoria). In addition, the eyes may be misaligned so that they appear crossed (strabismus). In some affected children, the eye(s) may become red and/or painful. The presence of a retinoblastoma may cause glaucoma, a condition marked by a rise in the pressure within the eyeball that prevents the normal drainage of fluid from the eye and potentially causes characteristic damage to the optic nerve. Retinoblastoma may affect one eye (unilateral) or both eyes (bilateral). Retinoblastomas occur in two forms – heritable and non-heritable. Bilateral forms are heritable and usually diagnosed at a younger age. In most affected children, retinoblastoma is non-heritable; it occurs spontaneously for no apparent reason.

In approximately 60 percent of children, the presenting sign of retinoblastoma is leukocoria. Initially, leukocoria may only be detectable at certain angles or under certain light conditions. Leukocoria is often seen on flash photography. Leukocoria can be caused by conditions other than retinoblastoma. The detection of leukocoria warrants an immediate evaluation by an eye specialist (ophthalmologist).

Chromosomes are located in the nucleus of human cells and carry the genetic information for each individual. Human body cells normally have 46 chromosomes, 23 of which are inherited from the mother and 23 of which are inherited from the father. Pairs of human chromosomes numbered from 1 through 22 are called autosomes and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated p and a long arm designated q. Chromosomes are further sub-divided into many bands that are numbered. For example, chromosome 13q14.1-q41.2 refers to bands 14.1-14.2 on the long arm of chromosome 13. The numbered bands specify the location of the thousands of genes that are present on each chromosome. The retinoblastoma gene RB1 is located on the long arm (q) of chromosome 13 (13q14.1-q14.2).

Although retinoblastoma is a rare disorder, it is the most common cancer of the eye in children, accounting for about 3% of all childhood malignancies. Retinoblastoma affects males slightly more often than females. The incidence in the United States and Europe is estimated to be 2-5 children per 1,000,000 people in the general population. The age-adjusted annual incidence for children aged 0-4 in the United States is 10-14 children per 1,000,000. This equates to about 1 in 14,000-18,000 live births. Incidence is the number of newly diagnosed people with a disorder identified in a given year. Two-thirds of children are affected before the age of 2 and more than 90% of retinoblastomas become apparent before the age of five years.

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

The diagnosis of retinoblastoma is made based upon a thorough clinical evaluation, detailed patient history, the identification of characteristic symptoms, and a variety of specialized tests. The presenting symptom is usually leukocoria. A complete examination of the interior of the eye (fundoscopic examination under anesthesia – EUA) may be performed to locate the presence of a tumor or tumors. Magnetic resonance imaging (MRIs) may be used to determine the extent of the tumor(s) and determine if the tumor has spread to surrounding structures or tissue. Ultrasonography may be used to rule out other conditions. Computed tomography (CT) scans are generally avoided because of the potential risk of additional radiation-induced tumors if the child has hereditary retinoblastoma.


Retinopathy of prematurity

Retinopathy of prematurity (ROP) is a potentially blinding disease affecting the retinas in premature infants. The retinas are the light-sensitive linings of the insides of the eyes. In infants born prematurely, the blood vessels that supply the retinas are not yet completely developed. Although blood vessel growth continues after birth, these vessels may develop in an abnormal, disorganized pattern, known as ROP. In some affected infants, the changes associated with ROP spontaneously subside. However, in others, ROP may lead to bleeding, scarring of the retina, retinal detachment and visual loss. Even in cases in which ROP changes cease or regress spontaneously, affected children may have an increased risk of certain eye (ocular) abnormalities, including nearsightedness, misalignment of the eyes (strabismus), and/or future retinal detachment. The two major risk factors for ROP are a low birth weight and premature delivery.

Retinopathy of prematurity (ROP) is characterized by abnormal and uncontrolled development of blood vessels in the back of the eye (i.e., the retina) in premature infants. The retina is the innermost tissue layer in which images are focused at the back of the eye; it contains light-responding nerve cells (rods and cones) that convert light images into nerve impulses, which are conveyed via the optic nerve to the brain. During fetal development–at about 16 weeks’ gestation*–blood vessels that supply the retina begin to bud from the center of the retina (i.e., near the optic nerve), gradually reaching the front edges (periphery) of the retina at about the time of normal delivery. Thus, when infants are born prematurely, this process is incomplete. (*Gestation is the period of time from fertilization to birth. Full term is the normal period of human gestation from about 38 to 42 weeks.) ROP occurs when the blood vessel development is abnormal, with disorganized branching of retinal vessels and anomalous interconnections.

The risk factors for ROP are not completely understood. However, ROP occurs exclusively in premature infants, particularly those who weigh less than 3 pounds, 5 ounces (1,500 grams) at birth and those born before 28 weeks’ gestation. In countries with less developed newborn care practices, severe ROP can occur in larger premature infants.

ROP is a leading cause of visual impairment and blindness in infants in many industrialized and middle-income countries. As noted above, an increased incidence of ROP in the 1940s and 1950s was shown to be due to the use of high concentrations of supplemental oxygen in premature infants. The number of cases decreased with measures to monitor oxygen blood levels carefully. However, with modern advances in care and technology in neonatal intensive care units (NICUs), the incidence of ROP has increased as more premature infants of lower birth weights survive. Careful control of blood oxygen levels reduces the risk of ROP without compromising measures necessary to sustain life. Again, supplementary oxygen alone does not appear to be sufficient for the development of ROP. (For more, see Causes above.)

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

The eyes of premature infants at risk for ROP should be examined thoroughly approximately four to six weeks after birth and regularly reexamined as required until retinal blood vessel growth is complete. Although specific guidelines vary, at-risk infants typically include those who are born before 30 weeks' gestation and those who weigh less than 1,500 grams at birth–or weigh more than 1,500 grams but are in unstable health with a high risk for ROP. Parents of premature infants should speak with their children's health care team by the time the infant is five weeks old about guidelines concerning at-risk infants and evaluations for evidence of ROP.


Retinoschisis

Retinoschisis means splitting of the eye’s retina into two layers. There are two forms of this disorder. The most common is an acquired form that affects both men and women. It usually occurs in middle age or beyond, although it can occur earlier, and it is sometimes known as senile retinoschisis. The other form is present at birth (congenital) and affects mostly boys and young men. It is known as juvenile, X-linked retinoschisis.

Retinoschisis is characterized by a reduction in visual acuity.  There may also be a loss of peripheral vision.   Very few people become totally blind from either form of the disorder, but some men with the juvenile form may ultimately have very poor vision.

The cause of acquired retinoschisis is not known.  Although it often occurs in middle age or beyond, it may appear in individuals as young as 20.

Senile retinoschisis usually affects people in their 50s, 60s or 70s, but it has been found in persons much younger.  It affects males and females in equal numbers.

Central serous chorioretinopathy is a retinal disorder that affects the central area of the retina (macula).  Its cause is unknown.

The diagnosis of retinoschisis is usually made during an examination of the back of the eye (fundus) where any splits, tears or rips may be seen.  One diagnostic tool is Optical Coherence Tomography (OCT), which that uses light waves to create images of the retina.


IgG4-related retroperitoneal fibrosis

IgG4相关性腹膜后纤维化

Retroperitoneal fibrosis is a rare inflammatory disorder in which abnormal formation of fiber-like tissue (fibrosis) occurs behind the membrane that lines the cavity of the abdomen (peritoneum). This abnormal tissue growth often spreads to affect the tubes that carry urine from the kidney to the bladder (ureters). Often these tubes become blocked by the excess tissue. Specific symptoms may vary depending upon the exact location of tissue growth and how far it spreads. In most cases the cause of this disorder is unknown (idiopathic).

The most common symptom of retroperitoneal fibrosis is pain in the lower back or abdomen. In many cases this pain is dull, vague and difficult to localize. Additional symptoms may be weight loss, fever, nausea, a low level of circulating red blood cells (anemia), and loss of appetite. Impaired movement of a limb may occur intermittently and abnormal yellow discoloration (pigmentation) of the skin and the whites of the eyes (jaundice) may be present. Swelling of one leg may also occur. Reduced blood flow to the leg may cause pain and discoloration.

The exact cause of retroperitoneal fibrosis is not known in about two-thirds of the affected individuals (idiopathic). A drug used in the treatment and prevention of migraine headaches (methysergide) may be the cause of this rare disorder in 12 percent of cases. Malignant tumors are associated with retroperitoneal fibrosis in eight percent of affected individuals. Tissue that has been injured by trauma or surgery may be a factor in some cases.

Retroperitoneal fibrosis affects males twice as often as females. The majority of cases occur in individuals between 40 and 60 years of age. However, the disorder can occur at any age, although it is extremely rare in children.

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

Carcinoid Syndrome is a rare, malignant disorder that affects the small bowel, pancreas, and/or stomach.  Slow growing tumors can spread to the lungs, liver and ovary.  Symptoms of this disorder may include flushing, diarrhea, wheezing, stomach pain, and blockage of arteries.  (For more information on this disorder, choose Carcinoid  as your search term in the Rare Disease Database.)

Treatment of retroperitoneal fibrosis depends on the location and extent of the tissue growth.


Rett Syndrome

The symptoms, progression, and severity of Rett syndrome can vary dramatically from one person to another. The disorder primarily affects females and most likely represents a spectrum of disease associated with mutations of the MECP2 gene. A wide range of disability can potentially be associated with Rett syndrome. Symptoms generally appear in stages. It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.

Approximately 90-95% of Rett syndrome cases are caused by identifiable mutations of the MECP2 gene. More than 200 different mutations have been identified. In 99% of cases, these mutations occur sporadically and are not possessed or transmitted by a child’s parents (de novo mutations). Therefore, in the vast majority of cases Rett syndrome is not an inherited disorder. In such cases, the parents have normal chromosomes and the mutation arises in one of the parent’s reproductive (germ) cells, usually on the paternal side.

Rett syndrome occurs almost exclusively in girls. The incidence of Rett syndrome in the United States is estimated to be 1 in 10,000 girls by age 12. Cases of Rett syndrome can go undiagnosed or misdiagnosed, making it difficult to determine the disorder’s true frequency in the general population. Rett syndrome is the second most common cause of severe intellectual disability after Down syndrome.

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

A diagnosis of Rett syndrome is based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation. A variety of specialized tests may be conducted to rule out other conditions that can cause similar symptoms. A set of updated diagnostic criteria was recently published (Neul et al 2010). The fulfillment of these diagnostic criteria can lead to a clinical diagnosis of Rett syndrome. The report also includes diagnostic criteria for variant forms of Rett syndrome.


Reye Syndrome

Reye syndrome is a rare disorder of childhood and adolescence. It primarily affects individuals under 18 years of age, particularly children from approximately age four to 12 years. In rare cases, infants or young adults may be affected. The disorder’s cause is unknown. However, there appears to be an association between the onset of Reye syndrome and the use of aspirin-containing medications (salicylates) in children or adolescents with certain viral illnesses, particularly upper respiratory tract infections (e.g., influenza B) or, in some cases, chickenpox (varicella). Although any organ system may be involved, Reye syndrome is primarily characterized by distinctive, fatty changes of the liver and sudden (acute) swelling of the brain (cerebral edema). Associated symptoms and findings may include the sudden onset of severe, persistent vomiting; elevated levels of certain liver enzymes in the blood (hepatic transaminases); unusually high amounts of ammonia in the blood (hyperammonemia); disturbances of consciousness; sudden episodes of uncontrolled electrical activity in the brain (seizures); and/or other abnormalities, leading to potentially life-threatening complications in some cases. Due to the potential association between the use of aspirin-containing agents and the development of Reye syndrome, it is advised that such medications be avoided for individuals under age 18 years who are affected by viral infections such as influenza or chickenpox.

The symptoms of Reye syndrome typically begin after a viral illness, particularly an upper respiratory infection (e.g, with influenza B virus) or, in some cases, chickenpox (varicella). Less commonly, Reye syndrome may develop after infection with other viral agents, such as influenza A or rubella. (For further information, please see the Causes section of this report below.)

The specific cause of Reye syndrome remains unknown. However, according to researchers, there appears to be an association between the condition’s onset and the administration of aspirin-containing medications (salicylates) in children or adolescents with certain viral illnesses. This typically includes upper respiratory tract infections caused by the influenza B virus or chickenpox (varicella). Less commonly, the development of Reye Syndrome has been reported in association with other viral infections, including influenza A, herpes simplex, rubella, or Epstein-Barr.

Reye syndrome is a rare disorder that appears to affect males and females in relatively equal numbers. The disorder occurs almost exclusively in individuals younger than age 18 years. Most cases occur at about age 6, with most affected individuals ranging in age from approximately four to 12 years. However, there have been rare instances in which Reye syndrome has affected infants and young adults. Evidence suggests that children and adolescents in rural and suburban areas appear to be affected more frequently than those in urban areas.

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

According to researchers, Reye syndrome should be suspected in any infants, children, or adolescents who experience severe, persistent vomiting in association with evidence of unexplained acute swelling of the brain. The condition may be diagnosed based upon a complete patient history, thorough clinical evaluation, characteristic physical findings, and the results of specialized laboratory tests.

According to reports in the medical literature, the mainstays of treatment include early diagnosis; prompt administration of intensive care as required; and measures to correct metabolic abnormalities and prevent or control increased pressure between the skull and brain (intracranial pressure [ICP]) secondary to cerebral edema.


Rheumatic fever

Rheumatic fever is an inflammatory disease that is rare in the United States but common in some other parts of the world. It primarily affects children between the ages of 6 and 16, and develops after an infection with streptococcal bacteria, such as strep throat or scarlet fever. About 5% of those with untreated strep infection will develop rheumatic fever.

The streptococcal infection that precedes rheumatic fever may or may not be noticeable as a sore throat.  After a latent period of two or three weeks, the patient may develop symptoms of rheumatic fever.  The most common symptoms are: sore throat; swollen, red tonsils; fever; headache; and joint and muscle aches, especially in the knees.

Although rheumatic fever is clearly linked to Group A streptococcal infections (strep throat), the exact mechanism causing the disorder is not well understood.  Strep throat is highly contagious, whereas rheumatic fever is not contagious.  People who have had rheumatic fever tend to develop flare-ups with repeated strep infections.

Rheumatic fever usually affects children between the ages of 6 and 16, but may occur among young adults as well.  Although outbreaks have steadily declined since the end of World War II in the United States as a result of the use of antibiotics such as penicillin and its derivatives, several outbreaks linked to a particularly virulent strain of streptococcal infection have occurred.

Symptoms of the following disorder can be similar to those of rheumatic fever.  Comparisons may be useful for a differential diagnosis:

Juvenile rheumatoid arthritis, also known as Still’s disease or chronic polyarthritis, is characterized by progressive pain and tenderness in one or more joints.  This disorder, which tends to affect girls more than boys, may begin abruptly with high fever, joint pain, and a variety of skin rashes. Normal growth may be diminished and the spleen and/or liver may become enlarged.  The exact cause is not known.  Some forms of arthritis are believed to be autoimmune disorders (the body’s natural defenses against invading organisms suddenly begin to attack healthy tissue).


Rhizomelic chondrodysplasia punctata

RCDP1 is the most common and best understood type. However, RCDP regardless of type may be categorized as classic which has more severe features and lower plasmalogen levels or nonclassic which has relatively mild features and higher plasmalogen levels.

RCDP is caused by changes (variants) in several different genes. These variants affect the function of peroxisomes, which are sac-like structures in cells associated with breakdown of fatty acids and synthesis of different molecules. These gene variants affect the production of plasmalogens, resulting in low plasmalogen levels. RCDP1 is also associated with the accumulation of phytanic acid which does not occur in other types. Individuals with classic RCDP have lower plasmalogen levels and are more severely affected than those with the nonclassic form.

RCDP is an ultra-rare condition that occurs in people of all racial or ethnic groups, but most reported patients are from northern Europe such as the UK, Germany, France, Italy, Spain or the Netherlands. In the United States and Western Europe, RCDP affects less than 1 in 100,000 livebirths.

More information on these conditions can be found in NORD’s Rare Disease Database.

RCDP may be suspected in a newborn baby based on physical features such as development of early-onset cataracts, relative shortening of the proximal limbs (rhizomelia), characteristic facial features or when imagining tests show characteristic skeletal abnormalities. RCDP is definitively diagnosed by biochemical and molecular testing.


Riboflavin transporter deficiency

The onset of signs and symptoms can range from infancy to early adulthood. One person reported in the medical literature first presented symptoms at 27 years of age, but most affected individuals show symptoms within the first few years of life. Infants and children often develop normally until symptoms first begin. Sometimes, an infection or fever will occur just before symptoms first begin. The specific signs and symptoms that develop and their severity and their progression can be very different from one person to another, even among members of the same family, but for most people who are affected, the first symptom is sensorineural deafness (hearing loss due to inner ear damage). Generally, the later the onset of symptoms, the milder the disorder is. Severe forms can progress rapidly and without treatment can be life-threatening.

Riboflavin transporter deficiency is caused by a variation in one of three genes – SLC52A1 gene (causing riboflavin transporter deficiency type 1), the SLC52A2 gene (riboflavin transporter deficiency type 2), and the SLC52A3 gene (riboflavin transporter deficiency type 3). Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a variation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body. The SLC52A1 and SLC52A3 proteins are primarily located in the small intestine while the SLC52A2 protein is located in the brain.

Riboflavin transporter deficiency is believed to affect females and males in equal numbers. The exact number of people who have this disorder is unknown. As of November 2017, about 165 affected individuals have been reported in the medical literature or to the Cure RTD Registry. Rare disorders like riboflavin transporter deficiency often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. Researchers believe that these disorders are underdiagnosed; one estimate suggests that at least 1 in 1,000,000 people in the general population have riboflavin transporter deficiency.

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

A diagnosis of riboflavin transporter deficiency is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. Riboflavin transporter deficiency has yet to be detected by newborn screening. A diagnosis is confirmed by molecular genetic testing. Molecular genetic testing can detect disease-causing variations in the genes known to cause these disorders, but is available only as a diagnostic service at specialized laboratories. Because riboflavin transporter deficiency is treatable, prompt diagnosis and early treatment is essential to prevent irreversible neurological damage. Riboflavin supplementation should be given immediately in individuals suspected of having these disorders, even before confirmation through molecular genetic testing.


Ring chromosome 4 syndrome

Ring chromosome 4 is a rare disorder that is typically characterized by loss (deletion) of genetic material from both ends of the 4th chromosome and joining of the chromosomal ends to form a ring. Associated symptoms and findings may vary greatly, depending on the location of lost genetic material and/or other factors. Some affected infants may have a low birth weight; growth delay; delays in the acquisition of skills requiring the coordination of mental and physical activities (psychomotor retardation); an abnormally small head (microcephaly); a broad, beaked nose; and/or various additional physical abnormalities that are present at birth (congenital anomalies). However, patients have also been reported in which ring chromosome 4 is primarily associated with growth delay, with no major physical anomalies and normal psychomotor development. Ring chromosome 4 is usually caused by spontaneous (de novo) errors very early in the development of the embryo that appear to occur randomly for unknown reasons (sporadically).

As noted above, associated symptoms and physical findings may be extremely variable from person to person. Some infants with ring chromosome 4 may have multiple characteristic features, such as a low birth weight, feeding difficulties, failure to grow and gain weight at the expected rate (failure to thrive), developmental delays, malformations of the skull and facial (craniofacial) region, heart defects and/or other physical abnormalities. In addition, certain features may be similar to those seen in individuals with Wolf-Hirschhorn syndrome, which is a chromosomal disorder characterized by partial deletion (monosomy) of the short arm (p) of chromosome 4 (partial monosomy 4p) or features similar to those seen in individuals with partial deletion (monosomy) of the long arm (q) of chromosome 4 (partial monosomy 4q. (For further information on this disorder, please see the Related Disorders section of this report below.) Other people with ring chromosome 4 may have few symptoms and be primarily affected by growth delays (failure to thrive), with no major physical anomalies.

In most affected individuals, ring chromosome 4 appears to result from loss (deletion) of genetic material from both ends of the 4th chromosome and a joining of the ends to form a ring. Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as p, a long arm identified by the letter q and a narrowed region at which the two arms are joined (centromere). Chromosomes are further subdivided into bands that are numbered outward from the centromere. For example, chromosome 4p16 refers to band 16 on the short arm of chromosome 4.

Since ring chromosome 4 was originally described, close to 50 cases have been reported in the medical literature. Males and females appear to be affected relatively equally.

Symptoms of the following disorders may be similar to those of ring chromosome 4. Comparisons may be useful for a differential diagnosis:

Wolf-Hirschhorn syndrome, also known as Wolf syndrome, is a rare chromosomal disorder in which there is partial deletion (monosomy) of the short arm (p) of chromosome 4 (4p). Although the size and location of the 4p deletion vary from person to person, it is believed that deletion of band 4p16.3 is the critical region leading to characteristic features of the disorder. Associated abnormalities typically include a low birth weight, growth delay, poor muscle tone (hypotonia) and delays in the acquisition of skills requiring the coordination of physical and mental activities (psychomotor delay). Most affected infants and children also have distinctive malformations of the skull and facial (craniofacial) region. These may include a small head (microcephaly) and high forehead; highly arched eyebrows; widely spaced eyes (ocular hypertelorism); vertical skin folds that cover the eyes’ inner corners (epicanthal folds); a beaked nose with an abnormally wide nasal bridge; a downturned mouth; an unusually short vertical groove in the middle of the upper lip (philtrum); and/or large, malformed ears. Due to these and/or additional craniofacial malformations, the face may appear relatively dissimilar from one side to the other (craniofacial asymmetry). Additional physical abnormalities may also be present. Such features may include abnormal deviation of one eye in relation to the other (strabismus); partial absence of tissue from the colored region of the eye (iris coloboma); incomplete closure of the roof of the mouth (cleft palate); undescended testes (cryptorchidism) and abnormal placement of the urinary opening on the underside of the penis (hypospadias) in affected males; structural malformations of the heart; sudden episodes of uncontrolled electrical activity in the brain (seizures); skeletal abnormalities; and/or other findings. Wolf-Hirschhorn syndrome usually appears to occur spontaneously (de novo) for unknown reasons very early in embryonic development. Less commonly, it may appear to result from a balanced translocation in one of the parents.


Robinow syndrome

acral dysostosis with facial and genital abnormalities

Robinow syndrome is an extremely rare inherited disorder that affects development of the bones and other parts of the body. There are two forms of Robinow syndrome that are distinguished by signs and symptoms, severity, mode of inheritance, and the genes associated with them. Autosomal recessive Robinow syndrome is more severe and is characterized by shortening of the long bones in the arms and legs; short fingers and toes; wedge-shaped spinal bones that leads to abnormal curvature of the spine (kyphoscoliosis); fused or missing ribs; short stature; and distinctive facial features that are sometimes described as fetal facies because the face is similar to the face of a developing fetus. Other features may include underdeveloped genitalia; dental problems; kidney or heart defects; or delayed development. Children with autosomal dominant Robinow syndrome have similar but milder features. Spine and rib anomalies are usually not present and short stature is less severe. Some individuals with autosomal dominant Robinow syndrome also have increased bone mineral density (osteosclerosis).

Autosomal recessive Robinow syndrome is characterized by short stature, characteristic facial features, skeletal abnormalities, and/or genital abnormalities. The range and severity of symptoms vary from person to person.

The autosomal recessive and autosomal dominant forms of Robinow syndrome are caused by changes (mutations) in different genes.

Autosomal recessive Robinow syndrome has been reported in fewer than 200 people in families from various ethnic backgrounds.

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

Diagnosis of Robinow syndrome is usually made shortly after birth based on physical findings including short stature, limb and genital abnormalities and characteristic facial features. Molecular genetic testing for mutations in the ROR2 gene is available to confirm the diagnosis of autosomal recessive Robinow syndrome.  Molecular genetic testing for mutations in the WNT5A gene and DVL1 gene is available to confirm the diagnosis of autosomal dominant Robinow syndrome.