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NORD is very grateful to Elaine Cochran, Nurse Practitioner, Lead Associate Investigator, National Institute of Diabetes Digestive and Kidney Diseases, Clinical Endocrinology Branch, National Institutes of Health, for assistance in the preparation of this report.
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.
Initial symptoms of Rabson-Mendenhall syndrome include abnormalities of the head and face (craniofacial region), abnormalities of the teeth and nails, and skin abnormalities such as acanthosis nigricans, a skin disorder characterized by abnormally increased coloration (hyperpigmentation) and "velvety" thickening (hyperkeratosis) of the skin, particularly of skin fold regions, such as of the neck, groin, and under the arms. In most cases, additional symptoms are present. Rabson-Mendenhall syndrome is inherited as an autosomal recessive trait.
The symptoms of Rabson-Mendenhall syndrome vary greatly from case to case. Some individuals may be affected more severely than others. The disorder can potentially cause life-threatening complications during childhood or adolescence. Affected individuals will not have all of 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 become apparent during the first year of life or early during childhood. Initial symptoms include failure to thrive, abnormalities of the teeth and nails including early eruption of teeth (premature dentition), abnormally large teeth (macrodontia), irregular and crowded teeth, and thickened nails. Individuals with Rabson-Mendenhall syndrome may also have a coarse, prematurely-aged facial appearance with an abnormally prominent jaw (prognathism). Affected individuals also have abnormally large ears, full lips, and a furrowed tongue.
Another early symptom of Rabson-Mendenhall syndrome is abnormally increased coloration (hyperpigmentation) and "velvety" thickening (hyperkeratosis) of the skin, particularly of skin fold regions, such as of the neck and groin and under the arms (acanthosis nigricans). Affected individuals may also have abnormally dry skin.
Additional symptoms associated with Rabson-Mendenhall syndrome may include abdominal swelling (distension) and abnormal enlargement of the clitoris in females and the penis in males. Affected individuals may experience excessive hair growth (hypertrichosis) and some females may exhibit a male pattern of hair growth (hirsutism). Deficiency or absence of fatty tissue (adipose tissue) may also be present. Some individuals may attain puberty at an abnormally early age (precocious puberty). Short stature is an additional characteristic that may also be observed.
Rarely, individuals with Rabson-Mendenhall syndrome may have an abnormally large pineal gland (pineal hyperplasia). The pineal gland is a tiny organ in the brain that secretes melatonin, a hormone that helps to regulate sleep cycles and metabolism and is involved with certain aspects of sexual development. Affected individuals often have altered melatonin secrete, which contributes to the development of certain symptoms associated with Rabson-Mendenhall syndrome.
Because individuals with Rabson-Mendenhall syndrome fail to use insulin properly they may experience abnormally high blood sugar levels (hyperglycemia) after eating a meal (postprandial) and abnormally low blood sugar levels (hypoglycemia) when not eating.
As children with Rabson-Mendenhall syndrome age they may develop more serious complications including diabetes mellitus, recurrent gastric ulcers, and benign cysts in the ovaries. Diabetes may result in individuals having decreased resistance to life-threatening infections. Another life-threatening complication called ketoacidosis may also occur, secondary to diabetes mellitus. Ketoacidosis is elevated levels of acids in the body accompanied by abnormal accumulation of ketone bodies. (Ketone bodies are chemical substances normally produced by fatty acid metabolism in the liver.)
Most individuals with Rabson-Mendenhall syndrome alsok have abnormalities affecting the kidneys, such as nephrocalcinosis.
Rabson-Mendenhall syndrome is inherited as an autosomal recessive trait with variable expressivity, which means the physical findings and symptoms associated with the disorder vary greatly in severity from one person to another.
Genetic diseases are determined by two genes, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent.
Investigators have determined that Rabson-Mendenhall syndrome may be caused by disruption or changes (mutations) of the insulin receptor gene. Insulin receptors are molecular structures on the surfaces of certain "target" cells that bind with insulin, triggering cellular response. In Rabson-Mendenhall syndrome, mutations 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.
The insulin receptor gene is located on the short arm (p) of chromosome 19 (19p13.2). 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" and a long arm identified by the letter "q." Chromosomes are further subdivided into bands that are numbered. For example, "chromosome 19p13.2" refers to band 13.2 on the short arm of chromosome 19.
In individuals with Rabson-Mendenhall syndrome, the body may attempt to compensate for insulin resistance by increasing insulin secretion, which may lead to excessive insulin levels in the blood (hyperinsulinemia). Hyperinsulinemia may result in certain features associated with Rabson-Mendenhall syndrome such as acanthosis nigricans, hypertrichosis, and polycystic ovaries. Conversely, and quite distinctively, despite these extremely high levels of insulin, triglyceride levels are strikingly low in affected individuals.
Rabson-Mendenhall syndrome affects males and females in equal numbers. Fewer than 50 cases 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 acanthosis nigricans with insulin resistance type A, are also caused by mutations in the insulin receptor gene. Some researchers believe that these three disorders represent a continuum or spectrum of disease. Rabson-Mendenhall would represent an intermediate form of the disorder.
Leprechaunism, also known as Donohue syndrome, is an extremely rare disorder characterized by abnormal resistance to insulin that results in a variety of abnormalities including growth delays and abnormalities affecting the endocrine system (i.e., the system of glands that secrete hormones into the blood system). Affected infants may also have distinctive abnormalities of the head and face (craniofacial) region, low birth weight, skin abnormalities, and abnormal enlargement of the breast and clitoris in females and the penis in males. In many cases, additional abnormalities may be present. Leprechaunism is more severe than Rabson-Mendenhall syndrome. Leprechaunism is inherited as an autosomal recessive trait. (For more information on this disorder, choose "leprechaunism" as your search term in the Rare Disease Database.)
Acanthosis nigricans (AN) is a skin disorder characterized by abnormally increased coloration (hyperpigmentation) and "velvety" thickening (hyperkeratosis) of the skin, particularly of skin fold regions, such as of the neck and groin and under the arms (axillae). Experts suggest that acanthosis nigricans may be a skin manifestation of insulin resistance, which is a condition characterized by impaired biological responses to insulin. Acanthosis nigricans with insulin Resistance type A is a rare form of acanthosis nigricans characterized by skin abnormalities; ; insulin resistance; increased levels of insulin in the blood (hyperinsulinemia); potential develop of diabetes; multiple cysts on the ovaries; increased secretion of male hormones known as androgens; and/or a male pattern of hair growth in females (hirsutism). (For more information on this disorder, choose "acanthosis nigricans" as your search term in the Rare Disease Database.)
Lipodystrophies are a group of rare metabolic disorders which can be either inherited or acquired. They are characterized by abnormalities in fatty (adipose) tissue associated with total or partial loss of body fat, abnormalities of carbohydrate and lipid metabolism, severe resistance to naturally occurring and synthetic insulin, and immune system dysfunction. These disorders are differentiated by degrees of severity, and by areas or systems of the body affected. Lipodystrophies can also be associated with other disorders and various developmental abnormalities. Unlike syndromes caused by mutations in the insulin receptor (Rabson-Mendenhall, leprechaunism, and Type A), high triglyceride levels are frequently observed in patients with lipodystrophy, and low HDL levels, as distinguishing laboratory findings, apart from the physical appearance. (For more information on these disorders, choose "lipodystrophy" as your search term in the Rare Disease Database.)
There is no specific treatment for individuals with Rabson-Mendenhall syndrome. The treatment of the disorder is directed toward the specific symptoms that are apparent in each individual (e.g., surgery may be performed to treat ulcers or dental abnormalities). Affected individuals may receive high doses of insulin or insulin sensitizers, but in most cases this therapy ultimately proves unsuccessful. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, dental specialists, and other health care professionals may need to systematically and comprehensively plan an affected child's treatment.
Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
High doses of recombinant insulin-like growth factor I (rhIGF-I) have been used to treat individuals with ketoacidosis due to severe insulin resistance. Treatment with rhIGF-I has demonstrated improvement in some affected individuals. More research is necessary to determine the long-term safety and effectiveness of this treatment for ketoacidosis due to severe insulin resistance.
Some individuals with Rabson-Mendenhall syndrome have been treated with biguanides, which are drugs that lessen the development of glucose in the liver and may lead to an increased number of insulin receptors. More research is necessary to determine the long-term safety and effectiveness of this treatment for Rabson-Mendenhall syndrome.
According to the medical literature, two siblings with Rabson-Mendenhall syndrome were treated with leptin, a protein hormone that plays a role in fat metabolism. Leptin therapy produced improvement in blood sugar levels when not eating (fasting hyperglycemia), in blood insulin levels (hyperinsulinemia), and glucose and insulin tolerance. More research is necessary to determine the long-term safety and effectiveness of leptin therapy in the treatment of individuals with Rabson-Mendenhall syndrome.
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Report last updated: 2013/03/15 00:00:00 GMT+0