Rabson-Mendenhall Syndrome

Disease Overview

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 head and facial differences (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 patients, additional symptoms are present. Infants are found to have very little fat and may not grow and gain weight at the expected rate (failure to thrive) despite frequent feedings. Rabson-Mendenhall syndrome is inherited in an autosomal recessive pattern.

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Synonyms

• Mendenhall syndrome

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Signs & Symptoms

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 become apparent during the first year of life or during early 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 a prominent jaw (prognathism). Affected individuals also have large ears, full lips and a furrowed tongue.

Another early symptom of Rabson-Mendenhall syndrome is 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 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 have excessive hair growth (hypertrichosis) and some females may have 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 early age (precocious puberty). Short stature is an additional characteristic that may also be observed.

Rarely, individuals with Rabson-Mendenhall syndrome may have an 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 cannot use insulin properly they may have high blood sugar levels (hyperglycemia) after eating a meal (postprandial) and low blood sugar levels (hypoglycemia) when not eating. Along with the high blood sugars after eating and frequent low blood sugars in the fasting state, the blood insulin level will be quite elevated.

As children with Rabson-Mendenhall syndrome age they may develop more serious complications including diabetes mellitus, enlarged, cystic ovaries and risk for dehydration. 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 accumulation of ketone bodies. (chemical substances normally produced by fatty acid metabolism in the liver.) Most individuals with Rabson-Mendenhall syndrome also have abnormalities affecting the kidneys, such as nephrocalcinosis.

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Causes

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.

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, along with an unexpectedly high adiponectin level (which would be typically low in this extreme degree of insulin resistance).

Rabson-Mendenhall syndrome is inherited in an autosomal recessive pattern with variable expressivity, which means the physical findings and symptoms associated with the disorder vary greatly in severity from one person to another.

Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, 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 gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

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Affected populations

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.

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Disorders with Similar Symptoms

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.

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 patients, additional abnormalities may be present. Leprechaunism is more severe than Rabson-Mendenhall syndrome. Leprechaunism is inherited in an autosomal recessive pattern. (For more information on this disorder, choose “leprechaunism” as your search term in the Rare Disease Database.)

Acanthosis nigricans with insulin resistance type A is a rare form of extreme insulin resistance 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). Like Rabson-Mendenhall syndrome, the lipid panels can have unusually normal findings not typical with such severe insulin resistance, such as low to normal triglyceride levels, high HDL levels. Additionally, the adiponectin level is elevated, whereas, in such a state of severe insulin resistance, it should be low. In type A insulin resistance, there is a variant in the insulin receptor gene, but often in the beta subunit, rather than the alpha subunit in Rabson Mendenhall syndrome, and though extreme, the degree of insulin resistance is not as extreme as Rabson Mendenhall syndrome. Patients tend to have normal height, no dental abnormalities or unusual facial features. (For more information on this disorder, choose “acanthosis nigricans” as your search term in the Rare Disease Database.)

Lipodystrophy is a group of rare metabolic disorders, also associated with extreme insulin resistance, 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 variants in the insulin receptor gene (Rabson-Mendenhall, leprechaunism and type A insulin resistance), 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.)

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Standard Therapies

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 cystic ovaries or dental abnormalities). Affected individuals may receive high doses of insulin or insulin sensitizers, but in most people 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 plan an affected child’s treatment systematically and comprehensively.

Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.

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Clinical Trials and Studies

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.

Some individuals with Rabson-Mendenhall syndrome have been treated with GLP-1 receptor agonists and GIP/GLP-1 receptor agonists, which work by lowering the amount of glucose the liver makes and increasing the amount of insulin the pancreas excretes. Additionally, these classes of drugs decrease appetite by slowing gastric emptying. Treatment has shown benefit in reducing the large daily insulin requirements patients have, to make their insulin regimen more manageable, in terms of decreasing the doses of insulin. More research is necessary to determine the long-term safety and effectiveness of this treatment for Rabson-Mendenhall syndrome.

Patients with Rabson-Mendenhall syndrome have also been treated with metreleptin, a recombinant human leptin hormone therapy, 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.

New therapies continue to direct treatment at improving non-insulin mediated pathways in the body to use glucose. Such new therapies are looking at the use of thyroid hormone to use such pathways to improve the body’s use of glucose without needing insulin. 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
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, in the main, contact: www.centerwatch.com

For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/

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References

JOURNAL ARTICLES
Simpkin A, Cochran E, Cameron F, et al. Insulin receptor and the kidney: Nephrocalcinosis in patients with recessive INSR mutations. Nephron Physiology 2014; 128: 55-61.

Brown RJ, Cochran, E, Gorden P. Metreleptin improves blood glucose in patients with insulin receptor mutations. J Clin Endo & Metab. 2013; E1749-E1756.

Skarulis MC, Celi FS, Mueller E, et al.Thyroid hormone induced brown adipose tissue and amelioration of diabetes in patient with extreme insulin resistance. J Clin Endo & Metab. 2010; 95: 256-262.

Semple RK, Sleigh A, Murgatroyd PR, et al. Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis. J Clin Invest. 2009; 119: 315-322.

McDonald A, Williams RM, Regan FM, Semple RK, Dunger DB. IFG-I treatment of insulin resistance. Eur J Endocrinol. 2007;157:S51-S56.

Harris AM, Hall B, Kriss VM, Fowlkes JL, Kiessling SG. Rabson-Mendenhall syndrome: medullary sponge kidney, a new component. Pediatr Nephrol. 2007;22:2141-2144.

Musso C, Cochran E, Moran SA, et al. Clinical course of genetic diseases of the insulin receptor (type A and Rabson-Mendenhall syndromes): a 30-year prospective. J Clin Endocrinol Metab. 2004;89:1548-1554.

Cochran E, Young JR, Sebring N, et al. Efficacy of recombinant methionyl human leptin therapy for the extreme insulin resistance of the Rabson-Mendenhall syndrome. J Clin Endocrinol Metab. 2004;89:1548-1554.

INTERNET
Rabson-Mendenhall Syndrome. Orphanet. January 2009. Available at: Orphanet: Rabson-Mendenhall syndrome Accessed May 21, 2024.

Rabson-Mendenhall Syndrome. Online Mendelian Inheritance in Man (OMIM). Entry No:262190; Last Update: 02/12/2024. Available at: http://omim.org/entry/262190 Accessed May 21, 2024.

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