Rabson-Mendenhall Syndrome: Monogenic insulin resistance
Brief Summary of Disease
Insulin is a crucial hormone produced in the body. When secreted from the pancreas, insulin regulates blood sugar levels by stimulating sugar uptake into our liver, muscle, and fat cells.1 Many disorders, including one of the most prevalent diseases in the planet, Diabetes Mellitus, are characterized by the inappropriate response of body tissues to this hormone.1 Individuals with Rabson-Mendenhall syndrome (RMS) have an extremely rare condition in which, although insulin is produced, the insulin receptors do not function properly; thus, the body is resistant to the hormone’s function.2,3 This change results in developmental issues arising across many organs of the body with ranging severity in symptom presentation. While the disease presentation is often severe, the disease is extremely rare, with fewer than 50 cases presented in medical literature, and is suggested to affect less than 1 in million people in the world.2 Therefore, a deeper understanding of the disease, its etiology, and improved treatments are required for patients.
Etiology & Pathology
RMS is an autosomal-recessive disorder, meaning that mutations must be inherited from both parents in order for the offspring to inherit the disease. Based on the limited number of cases reported in medical literature, a common factor contributing to the disease appears to be mutations in the insulin receptor gene (INSR).2 The gene codes for the receptor to which the hormone binds; the receptor is necessary as hormone-receptor interactions activate the signalling pathway inside cells which allows for insulin to exert its function. The specific mutation documented in this syndrome is a deficit in the receptor which completely inhibits insulin binding.4 Additionally, other mutations have been found to result in a reduction in the number of produced insulin receptors.3 The more extreme the mutations in the gene, the more severe the disease presentation would be.5 Thus, the lack of insulin activity as a result of the absence of proper receptor interactions then leads to the development of Diabetes mellitus and low blood glucose in patients when they have not ingested food.1
The secondary effect of resistance to insulin function is the production of excess insulin by the body. Consequently, a common observation in individuals with RMS is hyperinsulinemia, or the presence of high amounts of insulin in the blood. As such, in addition to the direct effects of the lack of insulin function in these patients, hyperinsulinemia itself can lead to other developmental issues. For instance, excess insulin can bind to IGF-1 receptors in the skin, which stimulates the reproduction of skin cells (dermatocytes).6 Dermatocyte proliferation results in an increase in the level of pigmentation, presenting as dark, thickened patches of skin in the folds of the neck, groin, and the armpits. In women, hyperinsulinemia can lead to polycystic ovary syndrome, a hormonal disorder characterized by increased levels of male hormones.
Symptoms
Infants born with RMS have characteristics common of other inherited metabolic disorders. Infants are generally smaller than normal prior to birth and often fail to thrive, meaning they do not grow according to their expected growth trend.2 Another symptom present is abnormalities of the teeth, such as early eruption, large teeth, or irregularly shaped teeth in addition to a coarse and aged facial appearence.3 A final early feature of the disease is the lack of subcutaneous (under the skin) fatty tissue.3 As mentioned before, a common feature of the condition is legions of velvety skin. This condition is known as acanthosis nigricans, in which the increased pigmentation produced by skin cells leads to the formation of dark, thick patches in the folds of the neck, groin, and under the arms.3
Hyperinsulinemia itself is hypothesized to increase the production of androgens (male hormones) in females, which in turn leads to the formation of cysts in the ovaries and excess hair growth.7 The lack of insulin function directly results in abnormally high levels of glucose after food intake while the high levels of insulin secretion presents as abnormally low levels of glucose when not eating.1 As time passes, more serious complications such as Diabetes mellitus ensues which can cause death if a buildup of toxic ketoacids in the body occurs.3
Diagnosis
Similar to how many biochemical genetics diseases are diagnosed, a combination of both clinical symptoms and laboratory tests are utilized to diagnose RMS. Initially, infants are screened for the common, early symptoms mentioned above, such as facial, dental, and skin abnormalities.3 Additional laboratory testing, including measurement of fasting blood glucose levels, hemoglobin A1C, or the glucose tolerance test can be used to confirm insulin resistance.1 To establish the diagnosis as RMS and to differentiate from similar conditions such as Donohue syndrome or type A insulin resistance, genetic testing and a genetic history should be taken to determine the mutations in the INSR gene.5
Prognosis
The spectrum of insulin resistance disorders includes type A insulin resistance (often undetected until adolescence), Donohue syndrome (often fatal in infancy), and RMS, which is intermediate in presentation.3 Individuals with RMS often live well into their teens, and those with less severe complications can live to reach twenty years old.
In a study by Musso et. al, 3 patients with RMS were followed for up to 30 years.8 All three patients were in the age range of 7 to 9 years old when originally included in the study data and presented with acanthosis nigricans, hyperandrogenism, and diabetes mellitus. The patients were also found to have high morbidity as the one case presented in this study expired due to pulmonary hypertension. As no specific treatments for RMS have been proposed and the results of this study demonstrates, a deeper understanding of the disease progression could yield comfort for patients and families.8
Treatment and Current Research
No practical treatment has been developed for individuals with RMS. Instead, therapies are intended to relieve symptoms of the disease. For instance, insulin or insulin sensitizers such as metformin may be given to individuals who have developed diabetes. In individuals with polycystic ovary syndrome, cystic ovaries need to be removed with surgery.3
A suggested treatment for RMS is leptin, a protein hormone which functions by inhibiting fat cells from storing energy in the form of triglycerides. Leptin therapy has actually been demonstrated to increase insulin sensitivity in patients and normalize blood glucose.9 In one study, leptin therapy was administered to two siblings with RMS.9 After being treated with leptin for almost 10 months, an approximately 50% drop in plasma glucose and insulin levels were observed.10 These studies indicate that new therapies are needed to direct treatment towards non-insulin mediated pathways of metabolism to improve the body’s energy use.
Niki Esfahanian
Relevant Resources
Diabetes Canada
A national foundation which leads the fight against Diabetes in Canada by organizing fund raisers, supporting research, and providing information to prevent the onset and consequences of Diabetes.
Juvenile Diabetes Research Foundation
An organization focusing on research to improve the lives of individuals with type 1 diabetes and to cure the disease. The foundation has goals to support cure, treatment, and preventative measures for T1D.
Works Cited
1. Wilcox G. Insulin and Insulin Resistance. Clin Biochem Rev. 2005;26(2):19-39.
2. Genetics Home Reference - NIH. Rabson-Mendenhall syndrome. https://ghr.nlm.nih.gov/condition/rabson-mendenhall-syndrome#genes. Published 2020. Accessed February 21, 2020.
3. National Organization for Rare Disorders. Rabson-Mendenhall Syndrome. https://rarediseases.org/rare-diseases/rabson-mendenhall-syndrome/. Published 2016. Accessed February 21, 2020.
4. Roach P, Zick Y, Formisano P, Accili D, Taylor SI, Gorden P. A novel human insulin receptor gene mutation uniquely inhibits insulin binding without impairing posttranslational processing. Diabetes. 1994;43(9),1096-1102.
5. Sinnarajah K, Dayasiri MBKC, Dissanayake NDW, Kudagammana ST, Jayaweera AHHM. Rabson Mendenhall Syndrome caused by a novel missense mutation. Int J Pediatr Endocrinol. 2016;2016(1):21. doi:10.1186/s13633-016-0039-1
6. Longo N, Wang Y, Smith SA, Langley SD, Dimeglio LA, Giannella-Neto D. Genotype-phenotype correlation in inherited severe insulin resistance. Hum Mol Genet. 2002;11(12):1465-1475.
7. Higgins SP, Freemark M, Prose NS. Acanthosis nigricans: a practical approach to evaluation and management. Dermatol Online J. 2008;14(9):2. http://www.ncbi.nlm.nih.gov/pubmed/19061584. Accessed February 22, 2020.
8. Dunaif A. Insulin Resistance and the Polycystic Ovary Syndrome: Mechanism and Implications for Pathogenesis*. Endocr Rev. 1997;18(6):774-800. doi:10.1210/edrv.18.6.0318
9. 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. Medicine (Baltimore). 2004;83(4):209-222. doi:10.1097/01.md.0000133625.73570.54
10. Cochran E, Young JR, Sebring N, DePaoli A, Oral EA, Gorden P. Efficacy of Recombinant Methionyl Human Leptin Therapy for the Extreme Insulin Resistance of the Rabson-Mendenhall Syndrome. J Clin Endocrinol Metab. 2004;89(4):1548-1554. doi:10.1210/jc.2003-031952
Cite This Article:
Esfahanaian N., Munoz MFH., & Rashid S. Rabson-Mendenhall Syndrome: Monogenic insulin resistance Illustrated by S. Chen. Rare Disease Review. February 2022. DOI: 10.13140/RG.2.2.19060.42888
