Information on the following diseases can be found in the Related Disorders section of this report:

• Leprechaunism
• Acanthosis Nigricans With Insulin Resistance Type A and Type B
• .

The symptoms of Rabson-Mendenhall syndrome vary greatly from case to case. Some individuals may be affected more severely than others. Affected individuals will not have all of the symptoms listed below. The disorder usually becomes apparent during the first year of life.

Initial symptoms of Rabson-Mendenhall syndrome include 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 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.

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.)
.

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 case to case.

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 recessive disorders, the condition does not occur unless an individual inherits the same defective 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 of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.

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.
.

Rabson-M endenhall syndrome affects males and females in equal numbers. Fewer than 50 cases have been reported in the medical literature. Because rare disorders like Rabson-Mendenhall syndrome often go unrecognized, these disorders are under-diagnosed, 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:

Leprechaunism 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 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 AN 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 nigricians characterized by skin abnormalities; dental 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). Acanthosis Nigricans With Insulin Resistance Type A results from genetic defects in the insulin receptor gene. (For more information on this disorder, choose “acanthosis nigricans” as your search term in the Rare Disease Database.)
.

Treatment
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). 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.
.

Recombinant insulin-like growth factor I (rhIGF-I) has 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.
.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:262190; Last Update:7/18/94.

Buyce ML., ed. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications; For: The Center for Birth Defects Information Services Inc; 1990:1069-71.

Sperling MA., ed. Pediatric Endocrinology. Philadelphia, PA: W. B. Saunders Company; 1996:258.

JOURNAL ARTICLES
Longo N, et al., Progressive decline in insulin levels in Rabson-Mendenhall syndrome. J Clin Endocrinol Metab. 1999;84:2623-9.

Araki S, Syndromes of severe insulin resistance. Nippon Rinsho. 1999;57:617-21.

Takahashi Y, et al., Two aberrant splicings caused by mutations in the insulin receptor gene in cultured lymphocytes from a patient with Rabson-Mendenhall’s syndrome. J Clin Invest. 1998;101:588-94.

Desbois-Mouthon C, et al., Major circardian variations of glucose homeostatsis in a patient with Rabson-Mendenhall syndrome and primary insulin resistance due to a mutation (Cys284-->Tyr) in the insulin receptor alpha-subunit. Peditr Res. 1997;42:72-7.

Krook A, et al., Mutant insulin receptors in syndromes of insulin resistance. Baillieres Clin Endocrinol Metab. 1996;10:97-122.

Quin JD, et al., The effect of recombinant insulin-like growth factor I on ketone body, lipid and apolipoprotein concentrations and its use to treat ketoacidosis in severe insulin resistance. Diabet Med. 1994;11:590-2.

Longo N, et al., Impaired growth in Rabson-Mendenhall syndrome: lack of effect of growth hormone and insulin-like growth factor-I. J Clin Endocrinol Metab. 1994;79:799-805.

Ando A, Rabson-Mendenhall syndrome. Nippon Rinsho. 1994;52:2641-2.

Muller-Wieland D, et al., An in-frame insertion in exon 3 and a nonsense mutation in exon 2 of the insulin receptor gene associated with severe insulin resistance in a patient with Rabson-Mendenhall syndrome. Diabetologia. 1993;36:1168-74.

Moncada VY, et al., Insulin-receptor biosynthesis in cultured lymphocytes from an insulin-resistant patient (Rabson-Mendenhall syndrome). Evidence for defect before insertion of receptor into plasma membrane. Diabetes. 1986;35:802-7.