Chronic Intestinal Pseudo-obstruction
NORD is very grateful to Edy E. Soffer, MD, Center for Digestive Diseases, GI Motility Program, Department of Gastroenterology, Cedars Sinai Medical Center, for the assistance in the preparation of this report.
Synonyms of Chronic Intestinal Pseudo-obstruction
- chronic idiopathic intestinal pseudo-obstruction
- pseudo-obstruction syndrome
- No subdivisions found.
Chronic intestinal pseudo-obstruction (CIP) is a rare, potentially disabling gastrointestinal disorder characterized by abnormalities affecting the involuntary, coordinated muscular contractions (a process called peristalsis) of the gastrointestinal (GI) tract. Peristalsis propels food and other material through the digestive system under the control of nerves, pacemaker cells and hormones. CIP usually results from abnormalities affecting the muscles or nerves that are involved in peristalsis. Consequently, peristalsis becomes altered and inefficient. The symptoms of CIP resemble those caused by mechanical obstruction of the small bowel. Mechanical obstruction refers to something (such as a tumor, scar tissue, etc.) physically blocking the passage of food and other material through the GI tract. In individuals with CIP no such physical obstruction is present, hence the term pseudo-obstruction. Common symptoms include nausea, vomiting, abdominal pain, abdominal swelling (distention) and constipation. Ultimately, normal nutritional requirements cannot be met leading to unintended weight loss and malnourishment. CIP can potentially cause severe, even life-threatening complications.
There is no agreed upon classification system for CIP and proposed classification systems tend to be complex and confusing. There are also many different causes of CIP, which only adds to the confusion. The unifying concept for CIP regardless of cause is an abnormality affecting the passage of food and other material through the digestive system (gastrointestinal motility). Generally, CIP is broken down into two main forms depending on whether the disorder involves the muscles (myopathic CIP) or nerves (neuropathic CIP) of the GI tract that are involved in peristalsis. Some researchers lump enteric dysmotility together with CIP. The prognosis of this separate yet similar condition is different from CIP. This report deals solely with the strict definition of CIP as a disorder that causes an "obstruction-like" picture.
The specific symptoms and severity of CIP can vary greatly from one person to another, depending, in part, on the exact location and extent of the disease within the gastrointestinal tract. Any area of the GI tract can potentially be affected, but the small bowel is most commonly affected. By definition, CIP is chronic in nature and individuals usually have continuous symptoms of bowel obstruction. However, affected individuals may also experience recurrent episodes or "acute attacks" during which time symptoms worsen and become more pronounced. In between such episodes, affected individuals may experience vague, nonspecific symptoms relating to the GI tract and bowel obstruction. In extremely rare cases, some affected individuals do not have symptoms in between such attacks.
It is important to note that affected individuals may not have all of the symptoms discussed below and that the severity of the disorder can vary dramatically. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.
Children generally show symptoms of CIP at birth and may have a severe expression of the disorder. In less severe cases, symptoms may not develop until months later. Some symptoms may be intermittent and may only occur during an acute crisis or episode. In severe cases, CIP can potentially cause significant, life-threatening complications during infancy or early childhood.
Common symptoms include nausea and vomiting, abdominal swelling or bloating (distention), abdominal cramps, abdominal pain and constipation. Although constipation is more common, some affected individuals may experience a complete lack of bowel movements and have no gas in the GI tract (lack of flatus). Abdominal pain may be chronic in some cases while in other cases it may only occur during acute episodes. Abdominal pain has been described as either sharp or stabbing versus a dull ache or general discomfort. Some infants and children may also experience early fullness (satiety), an aversion to food and eating, and unintended weight loss or poor weight gain. Over time, bacterial infections and poor absorption of nutrients (malabsorption) may occur, ultimately resulting in malnutrition. Less often, diarrhea may occur, most likely due to bacterial infection.
The progression and natural history of CIP is not well studied in adults. Most likely, affected individuals have vague, non-specific gastrointestinal complaints for years before a diagnosis of CIP is suspected. Recurrent and severe abdominal pain may be the most common symptom in adults. Adults may also experience nausea and vomiting, constipation, and abnormal swelling or bloating of the abdomen. Unintended weight loss and loss of appetite may also develop. Eventually, affected individuals may experience bacterial infections, malabsorption and malnutrition. In severe cases, affected individuals can develop cachexia - a physical wasting syndrome characterized by loss of weigh and muscle mass.
In both children and adults additional symptoms can occur. Involvement of the esophagus can result in difficulty swallowing (dysphagia), chest pain and heartburn. In some cases, CIP may affect the urinary tract or bladder causing symptoms such as widening of the small tubes that carry urine from the kidneys (ureters) and difficulty urinating (dysuria). This occurs more often in myopathic CIP than in neuropathic CIP.
CIP is generally broken down into primary CIP, in which there is an intrinsic defect affecting the muscles or nerves that control the passage of food and other material through the GI tract, and secondary CIP, in which the disorder results from another, underlying non-gastrointestinal disorder or condition. In many cases the cause of CIP is unknown; these cases may be categorized as idiopathic and are sometimes referred to as chronic idiopathic intestinal pseudo-obstruction (CIIP).
Primary CIP is further broken down into two subgroups - myopathic CIP and neuropathic CIP - depending on whether the condition results primarily in abnormalities of muscles within the GI tract (visceral myopathy) or abnormalities of nerves within the GI tract (visceral neuropathy). A variety of poorly understood familial and acquired disorders that damage intestinal muscle or nerves can cause primary CIP. Consequently, primary CIP may also be separated by three additional subcategories - congenital (present at birth), familial (most likely genetic), and sporadic (seemingly occurring at random). Familial cases of primary CIP may be inherited as an autosomal dominant, autosomal recessive or an X-linked trait. Several disease genes (genetic mutations) have been identified in these familial cases. Most adult cases of CIP are sporadic and secondary; most childhood cases are primary and sporadic.
A wide variety of systemic, metabolic and organic diseases have been associated with secondary CIP. Such diseases including a group of autoimmune disorders called collagen vascular diseases including scleroderma, lupus, dermatomyositis, mixed connective tissue disorder and rheumatoid arthritis; endocrine disorders including diabetes mellitus, hypothyroidism or hypoparathyroidism; neurological disorders including Parkinson disease, multiple system atrophy, and Hirschsprung's disease; certain cancers causing paraneoplastic syndromes such as small cell carcinoma of the lung; muscle disorders (myopathies), including desmin myopathy, Duchenne muscular dystrophy or myotonic dystrophy; or additional disorders such as amyloidosis, Celiac disease, Ehlers-Danlos syndrome or mitochondrial neurogastrointestinal encephalopathy (MNGIE).
Infections including Chagas disease, Epstein Bar virus, or cytomegalovirus can also result in secondary CIP. CIP can also occur secondary to the use of certain drugs or medications such as tricyclic antidepressants, anticholingergic agents or narcotics.
CIP can also develop before birth (in utero) in select cases due to toxins or insults affecting the developing fetus. One such cause of CIP developing in utero is fetal alcohol syndrome.
The symptoms of CIP are caused by abnormalities affecting muscle or nerves within the gastrointestinal tract. When the abnormality results in weakened or absent contractions, it is classified as myopathic. When the abnormality results in unsynchronized contractions, it is classified as neuropathic.
Myopathic CIP is caused by injury to the smooth muscle of the GI tract. Smooth muscles are involuntary muscles - the brain has no conscious control over them. Smooth muscles react involuntarily to various stimuli. Smooth muscle lines the walls of the GI tract and helps to control the wave-like contractions (peristalsis) that aids in the digestion and transport of food.
Neuropathic CIP is usually caused by damage to the enteric nervous system, which is sometimes referred to as the brain in the gut. The nerves of the enteric nervous system are embedded in the walls of the digestive tract all the way from the esophagus to the anus. The enteric nervous system is involved in various processes in the GI tract including peristalsis and is vital to overall health and well-being. Less often, neuropathic CIP can be caused by abnormalities affecting other nerve cells in the GI tract.
In some cases, CIP is caused by damage to the interstitial cells of Cajal (ICC), which are the pacemaker cells of the GI tract. These cells are now known to be critical for proper GI motility. Interstitial cells of Cajal help to generate and maintain electrical rhythmic activity within the GI tract. Interstitial cells of Cajal also play a role in amplifying signals from nerve cells (neurons) to smooth muscle cells. Individuals with CIP due to abnormalities of these cells have signs of both muscle and nerve disease in the GI tract.
Examination of tissue from the gut of patients with CIP showed that commonly, both the muscle and nerves are affected by the disease process.
CIP affects males and females in equal numbers and can affect individuals of any age. The prevalence of CIP in the general population is unknown. According to some sources approximately 100 new cases of CIP are reported in children in the United States each year. However, CIP often goes unrecognized or misdiagnosed making it extremely difficult to determine the true frequency of CIP in the general population. Children are predominantly affected by primary, non-familial, sporadic CIP. Adults are generally affected by secondary CIP, most often due to systemic diseases such as scleroderma, diabetes, or paraneoplastic syndromes.
Symptoms of the following disorders can be similar to those of CIP. Comparisons may be useful for a differential diagnosis.
The signs and symptoms of mechanical obstruction of the GI tract are virtually indistinguishable from those associated with CIP. Such symptoms include abdominal pain and bloating, nausea and vomiting and constipation. Mechanical obstruction can be caused by a variety of conditions including adhesions (scar tissue), foreign (ingested) material, gallstones, tumors, hernia, abnormal tissue growth, twisting of a loop of the intestines back around itself (volvulus), and intussusception, a condition in which one portion of the intestines slides into another much like a collapsing telescope. It is extremely important to distinguish CIP from mechanical obstruction of the GI tract as the underlying process and potential treatments are different.
Ogilvie syndrome, also known as acute colonic pseudo-obstruction, is a rare disorder characterized by abnormalities affecting the involuntary, rhythmic muscular contractions (a process called peristalsis) within the colon of the large intestines. Peristalsis propels food and other material through the digestive system through the coordination of muscles, nerves and hormones. Symptoms are similar to other forms of intestinal pseudo-obstruction and can include nausea, vomiting, abdominal bloating or swelling and constipation. The symptoms of Ogilvie syndrome mimic those of a mechanical obstruction of the colon, but no such physical obstruction is present. Ogilvie syndrome is usually associated with an underlying disorder or due to trauma or surgery. (For more information on this disorder, choose "Ogilvie" as your search term in the Rare Disease Database.)
A variety of gastrointestinal disorders can have signs and symptoms that are similar to those seen in CIP. Such disorders include irritable bowel syndrome (IBS), gastroparesis, functional dyspepsia, Crohn's disease, and cyclic vomiting syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
A diagnosis of CIP is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests to rule out other conditions or identify underlying causes. Symptoms of CIP should be present for at least six months before a diagnosis of CIP can be made.
Clinical Testing and Work-Up
A variety of laboratory tests may be performed such as a complete blood count to check for anemia or infection; erythrocyte sedimentation (SED) rate, which measures how much inflammation is in the body; tests to determine the levels of serum electrolyte, thyroid hormone levels, and albumin; tests to determine how long it takes the blood to clot, which can be abnormal in individuals with bacterial overgrowth or significant nutritional deficiencies; and certain antibody tests that can be used to rule out other conditions or identify underlying causes of CIP.
CIP is virtually indistinguishable from mechanical obstruction based solely on signs and symptoms. X-ray examination of the GI tract will be performed to rule out mechanical obstruction. Plain abdominal films can reveal widened (distended) bowel loops and air-fluid levels, which may also be present in intestinal obstruction and are necessary for a diagnosis of CIP. If such evidence of obstruction is found, a barium contrast study is usually performed on the entire GI tract to help rule out or identify a mechanical obstruction. Barium studies can also reveal absent or abnormal peristalsis. Ruling out short bowel obstruction is the most important distinction to make when diagnosing CIP. Short bowel obstruction is more common than CIP and can be treated surgically.
Additional x-ray studies may be necessary in some cases. An upper gastrointestinal endoscopy may also be performed to rule out mechanical obstruction in the upper GI tract. During this examination, a device known as an endoscope is run down the throat. An endoscope is a thin, flexible tube that has a small camera with a light on its tip and allows a physician to examine the tissue of the lower esophagus and the junction where the esophagus meets the stomach.
Computerized tomography (CT) scanning and magnetic resonance imaging (MRI) of the abdomen may also be performed. During abdominal CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures within the abdomen. An abdominal MRI uses a magnetic field and radio waves to produce cross-sectional images of the abdomen.
Following x-ray studies of the GI tract, physicians may then perform a GI transit study (scintigraphy), which measures the rate at which materials travel through the digestive system. After GI transit studies, a manometry may be performed. Manometry is an examination that measures pressure or contractions within the intestinal tract. Manometry can provide further evidence for a diagnosis of CIP and can help determine the underlying cause. An esophageal manometry may also be performed to detect abnormalities of esophageal motility.
Some physicians may recommend surgical removal and microscopic study of tiny amounts of GI muscle and nerve tissue (full thickness biopsy). However, the use of full thickness biopsies in the diagnosis of CIP is controversial. They require a surgical procedure known as a laparotomy to obtain the affected tissue of the bowel wall and according to some reports can potentially worsen gastrointestinal motility problems. However, such biopsies can uncover additional information about the underlying cause of the disorder and reveal the specific cells involved. Prompt diagnosis of CIP is important as delays in proper diagnosis have often led to unnecessary and potentially harmful surgical procedures.
There is no specific treatment for individuals with CIP. Treatment is directed toward the specific symptoms that are apparent in each individual, and to support adequate nutritional needs. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, pediatric gastroenterologists, surgeons, pain management specialists, psychologists, dietitians, and other healthcare professionals may need to systematically and comprehensively plan an affect individual's treatment.
The specific therapeutic procedures and interventions for individuals with CIP will vary, depending upon numerous factors including the specific symptoms present, the site and extent of the affected portion of the GI tract, an individual's age and overall health, tolerance of certain medications or procedures, personal preference and other factors. Decisions concerning the use of particular therapeutic interventions should be made by physicians and other members of the healthcare team in careful consultation with the patient and/or parents based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.
In individuals with secondary CIP, treatment of the underlying disorder is mandatory and can provide relief of CIP symptoms. Treatment options for individuals with primary or idiopathic CIP are complex and varied and often prove difficult. The specific treatment plan may be highly individualized and can include can dietary adjustments, total parenteral nutrition (TPN), enteral feeding, certain medications and surgery.
Individuals with CIP are encouraged to eat five to six small meals a day rather than three large ones and to follow a low-fat, low-fiber diet. Such a diet may emphasize liquids and soft foods. Fatty foods are believed to delay gastric emptying. High fiber foods are thought to be associated with abdominal bloating and discomfort. Some physicians recommend avoiding lactose because of the high incidence of lactose intolerance in the general population. Affected individuals may also be encouraged to follow a low-residue diet, which limits foods that leave undigested parts in the GI tract (these undigested parts normally become part of stool). A low-residue diet is similar, but generally more restrictive than a low fiber diet.
Affected individuals may also need to take daily multivitamins and nutritional supplements, which are beneficial for individuals who experience nutritional deficiencies and/or malnourishment.
A variety of different medications may be used to treat individuals with CIP. Medications can help to control symptoms and to avoid complications. Antibiotics may be prescribed to treat bacterial infections and can help relieve diarrhea and bloating. Drugs that are effective against nausea and vomiting (antiemetics) may also be used.
Prokinetics are a class of drugs that are often prescribed to individuals with CIP with the intent of improving gastrointestinal motility. Prokinetics improve gastrointestinal motility by increasing the frequency of contractions in the small intestines without disrupting their rhythms. They have proven beneficial in some cases, but overall their effectiveness has been limited. Examples of prokinetic drugs are erythromycin, metoclopramide, domeperidone, otreotide, tegaserod and lubiprostone. A drug called cisapride is a prokinetic agent that has been used to treat CIP in the past, but is no longer widely available after being voluntarily pulled from the market in 2000 because of an association with serious cardiac arrhythmias.
Low-dose tri-cyclic antidepressants and gabapentin have been used to treat chronic pain. Pain medications classified as narcotics are avoided because they can further deteriorate digestive function.
Enteral or Total Parenteral Nutrition
Some individuals and children may be unable or unwilling to eat because of the severity of their disorder or they may be unable to maintain basic nutritional requirements even with supplementation and diet adjustments. In such cases, individuals are put on enteral or total parenteral nutrition (TPN). Enteral feeding is the use of a tube to deliver food directly into the stomach or small bowel. Eventually, affected individuals are given small amounts of food orally. It is important that infants receive small amounts of food orally in order for the infant to learn how to suck and to eat.
TPN supplies all daily nutritional requirements such as protein, sugars, vitamins, minerals, carbohydrates and sometimes fats. TPN is a way to bypass how the body normally digests food. With TPN, a special intravenous (IV) line is inserted into a vein and nutrients are delivered directly into the bloodstream. The first dose of TPN is given at a hospital. Eventually, TPN is given at home. The amount of time a person requires TPN varies. TPN is more costly and dangerous than enteral feeding and every attempt should be made when possible to use the enteral path first.
Some individuals with CIP may be treated by intestinal decompression, a procedure that reduces the pressure within the GI tract. Intestinal decompression is most commonly performed by inserting a tube within the intestines allowing physicians to decompress abnormally swollen (distended) segments of the intestines. Intestinal decompression can improve transport capacities and can result in a reduced rate of hospitalization for affected individuals. Bowel decompression may also be used to treat abdominal pain. In some cases, venting enterstomy can assist in relieving abdominal swelling and bloating. A venting enterstomy is a procedure in which the small intestines are diverted to an artificial opening in the abdominal wall.
Rarely, and in very specific and severe cases of CIP, surgery to remove a section of the intestines may be necessary. Because surgery can potentially worsen CIP, it only has a limited role in the treatment of specific cases. When CIP is limited to an isolated portion of the bowel, surgical bypass of the affected segment may be beneficial. Certain surgeries such as the surgical removal of a segment of the intestines (enterectomy) or the surgical creation of a passage between the duodenum and jejunum can potentially decrease the frequency certain symptoms such retching, vomiting and abdominal distention.
In extremely severe cases, such as for individuals who do not respond to other treatments (refractory disease), who were unable to maintain proper nutrition with other therapies, who are dependent on TPN, or who experience complications from TPN such as liver failure, small bowel transplantation may be an option. During a small bowel transplant, the affected portion of the small bowel is removed and replaced with one from a healthy donor. A variety of complications can occur with small bowel transplantation including organ rejection, infections, and lymphoproliferative disease. In addition, the procedure is expensive and requires the continued use of immunosuppressive drugs to lessen the chance of rejection. However, as surgical techniques and immunosuppressive agents improve in efficacy, survival has improved as well.
Researchers are currently studying the use of intestinal pacemakers, which operate on the same principal of cardiac pacemakers. Intestinal pacemakers use high frequency electrical stimulation to deliver a series of electrical pulses to the GI tract. Initial studies have been conducted on a related gastrointestinal motility disorder called gastroparesis. Early results have shown improvements in nausea and vomiting associated with that condition. More research is necessary to determine whether intestinal pacemakers will be effective in treating gastrointestinal motility disorders like CIP.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, in the main, contact:
Chronic Intestinal Pseudo-obstruction Resources
NORD Member Organizations:
(To become a member of NORD, an organization must meet established criteria and be approved by the NORD Board of Directors. If you're interested in becoming a member, please contact Susan Olivo, Membership Manager, at firstname.lastname@example.org.)
Rosemore J, Lacy BE. Chronic Intestinal Pseudo-Obstruction. In: Advanced Therapy in Gastroenterology and Liver Disease, 5th ed, Bayless, Diehl, editors. 2005 BC Decker, Inc. Hamliton, Ontario. Pp.375-380.
Faure C. Chronic Intestinal Pseudo-Obstruction. In: Pediatric Gastrointestinal Disease, 4th ed, Walter, Goulet, Kleinman, Sherman Schneider, Sanderson, editors. 2004 BC Decker, Inc. Hamliton, Ontario. Pp. 1044-1054.
Sanaka MR, Soffer EE. Intestinal Pseudoobstruction in Adults. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:347.
Hyman PE, Sood M. Intestinal Pseudoobstruction (Pediatric Presentation). In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:348-349.
Lee BH, Kim N, Kang SB, et al. Two cases of chronic idiopathic intestinal pseudo-obstruction with different clinical features. J Neurogastroenterol Motil. 2010;16:83-89. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879827/
Lacy BE, Lowe BJ. Diagnosis, treatment and nutritional management of chronic intestinal pseudo-obstruction. Practical Gastroenterlogy. 2009;9-24. http://www.medicine.virginia.edu/clinical/departments/medicine/divisions/digestive-health/nutrition-support-team/nutrition-articles/LacyArticleAug09.pdf
Lindberg G, Iwarzon M, Tornblom H. Clinical features and long-term survival in chronic intestinal pseudo-obstruction and enteric dysmotility. Scand J Gastroenterol. 2009;44:692-699. http://www.ncbi.nlm.nih.gov/pubmed/19308797
Lingberg G, Tornblom H, Iwarzon M, et al. Full-thickness biopsy findings in chronic intestinal pseudo-obstruction and enteric dysmotility. Gut. 2009;58:1084-1090. http://www.ncbi.nlm.nih.gov/pubmed/19136514
Antonucci A, Fronzoni L, Cogliandro L, et al. Chronic intestinal pseudo-obstruction. World J Gastroenterol. 2008;14:2953-2961. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2712158/
Stanghellini V, Cogliandro RF, DeGiorgio R, et al. Chronic intestinal pseudo-obstruction: manifestations, natural history and management. Neurogastroenterol Motil. 2007;19:440-452. http://www.gemd.org/filesupload/contenido_subsubapartado/14_30_2-estomago--intestino_pseudoobstruccion-cronica-intestinalpdf_contenido_subsubapartado.pdf
Munoz MT, Solis Herruzo JA. Chronic intestinal pseudo-obstruction. Rev Esp Enferm Dig. 2007;99:100-111. http://www.ncbi.nlm.nih.gov/pubmed/17417923
Connor FL, Di Lorenzo C. Chronic intestinal pseudo-obstruction: assessment and management. Gastroenterology. 2006;130:S29-S36. http://www.ncbi.nlm.nih.gov/pubmed/16473068
De Giorgio R, Sarnelli G, Corinaldesi R, Stanghellini V. Advances in our understanding of the pathology of chronic intestinal pseudo-obstruction. Gut. 2004;53:1549-1552. http://www.ncbi.nlm.nih.gov/pubmed/15479666
FROM THE INTERNET
National Digestive Diseases Information Clearinghouse. Intestinal Pseudo-Obstruction. January 2008. Available at: http://digestive.niddk.nih.gov/ddiseases/pubs/intestinalpo/ Accessed On: July 12, 2011.
Chronic Intestinal Pseudo-obstruction. Orphanet encyclopedia, January 2007. Available at: http://www.orpha.net Accessed on: July 12, 2011.
The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.
The National Organization for Rare Disorders (NORD) web site, its databases, and the contents thereof are copyrighted by NORD. No part of the NORD web site, databases, or the contents may be copied in any way, including but not limited to the following: electronically downloading, storing in a retrieval system, or redistributing for any commercial purposes without the express written permission of NORD. Permission is hereby granted to print one hard copy of the information on an individual disease for your personal use, provided that such content is in no way modified, and the credit for the source (NORD) and NORD’s copyright notice are included on the printed copy. Any other electronic reproduction or other printed versions is strictly prohibited.
Copyright ©1987, 1988, 1989, 1994, 2003, 2012
Report last updated: 2012/01/05 00:00:00 GMT+0
NORD's Rare Disease Information Database is copyrighted and may not be published without the written consent of NORD.