A novel insulin receptor mutation in an adolescent with acanthosis nigricans and hyperandrogenism
-
Mansa Krishnamurthy
and
Mia M Pingul
Abstract
Insulin receptor mutations cause extreme insulin resistance resulting in acanthosis nigricans and hyperandrogenism. We report a pre-menarchal adolescent female with normal weight, with severe acanthosis nigricans, acne, and hirsutism. Initial investigation revealed elevated fasting and post-prandial insulin and high testosterone and androstenedione levels. Her father had frequent complaints of hypoglycemia. Coding sequence and splice junction analysis of the INSR gene, in our patient and her father, revealed a heterozygous missense mutation in the β subunit of the insulin receptor (Arg1131Trp), resulting in receptor loss of function. Metformin therapy and carbohydrate control improved acanthosis and menarche ensued within 3 months. Our case highlights the importance of distinguishing insulin resistance commonly associated with obesity from monogenic defects. Although, there is no consensus on treatment of children with monogenic forms of insulin resistance due to its rarity, dietary and lifestyle modifications and insulin-sensitizing agents play a key role in management.
Acknowledgments
We are grateful to Dr. Robert K. Semple and his laboratory for sequencing the INSR gene. The authors have nothing to disclose.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in thestudy design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Reaven GM. Role of insulin resistance in human disese. Diabetes 1988;37:1595–607.10.2337/diab.37.12.1595Search in Google Scholar
2. Acilli D, Barbetti F, Cama A, Kadowaki H, Kadowaki T, et al. Mutations in the insulin receptor gene in patients with genetic syndromes of insulin resistance and acanthosis nigricans. J Invest Derm 1992;98:77S–81.10.1111/1523-1747.ep12462281Search in Google Scholar
3. Raffan E, Soos MA, Rocha N, Tuthill A, Thomsen AR, et al. Founder effect in the Horn of Africa for an insulin receptor mutation that may impair receptor recycling. Diabetologia 2011;54:1057–65.10.1007/s00125-011-2066-zSearch in Google Scholar
4. Kuroda Y, Iwahashi H, Mineo I, Fukui K, Fukuhara A, et al. Hyperinsulinemic hypoglycemia syndrome associated with mutations in the human insulin receptor gene: report of two cases. Endocrine J 2015;62:353–62.10.1507/endocrj.EJ14-0547Search in Google Scholar
5. Moghetti P, Toscano V. Treatment of hirsutism and acne in hyperandrogenism. Best Pract Res Clin Endocrinol Metab 2006;20:221–34.10.1016/j.beem.2006.03.003Search in Google Scholar
6. Vissing AC, Taudorf EH, Haak CS, Philipsen PA, Haedersdal M. Adjuvant eflornithine to maintain IPL-induced hair reduction in women with facial hirsutism: a randomized control trial. J Eur Acad Dermatol Venereol 2016;30:314–9.10.1111/jdv.13447Search in Google Scholar
7. Fradkin JE, Eastman RC, Lesniak MA, Roth J. Specificity spillover at the hormone receptor – exploring its role in human disease. NEJM 1989;320:640–5.10.1056/NEJM198903093201005Search in Google Scholar
8. Taylor SI, Dons RF, Hernandez E, Roth J, Gorden P. Insulin resistance associated with androgen excess in women with autoantibodies to the insulin receptor. Ann Int Med 1982;97:851–5.10.7326/0003-4819-97-6-851Search in Google Scholar
9. Barbieri RL, Ryan KJ. Hyperandrogenism, insulin resistance and acanthosis nigricans syndrome: a common endocrinopathy with distinct pathophysiological features. Am J Ob Gyn 1983;147:90–101.10.1016/0002-9378(83)90091-1Search in Google Scholar
10. Rosenberg AM, Haworth JC, Degroot GW. A case of leprechaunism with severe hyperinsulinemia Am J Dis Child 1980;134:170–5.10.1001/archpedi.1980.02130140044014Search in Google Scholar PubMed
11. Dominguez-Garcia A, Martinez R, Urrutia I, Garin I, Castano L. Identification of a novel insulin receptor gene heterozygous mutation in a patient with type A insulin resistance syndrome. J Pediatr Endocrinol Metab 2014;27:561–4.10.1515/jpem-2013-0284Search in Google Scholar
12. Ardon O, Procter M, Tvrdik T, Longo N, Mao R. Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene. Mol Gen Metab Reports 2014;1:71–84.10.1016/j.ymgmr.2013.12.006Search in Google Scholar
13. Thorton PS, Satin-Smith MS, Herold K, Glaser B, Chiu KC, et al. Familial hyperinsulinism with apparent autosomal dominant inheritance: clinical and genetic differences from autosomal recessive variant. J Pediatrics 1998;132:9–14.10.1016/S0022-3476(98)70477-9Search in Google Scholar
14. Højlund K, Hansen T, Lajer M, Henriksen JE, Levin K, et al. A novel syndrome of autosomal-dominant hyperinsulinemic hypoglycemia linked to a mutation in the human insulin receptor gene. Diabetes 2004;53:1592–8.10.2337/diabetes.53.6.1592Search in Google Scholar PubMed
15. Scholl JH, van Eekeren R, van Pijenbroek EP. Six cases of (severe) hypoglycemia associated with gabapentin use in both diabetic and non-diabetic patients. Br J Clin Pharmacol 2015;79:870–1.10.1111/bcp.12548Search in Google Scholar PubMed PubMed Central
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Articles in the same Issue
- Frontmatter
- Review
- An update on thyroid-associated ophthalmopathy in children and adolescents
- Mini Review
- Systematic review and meta-analysis of the association between mumps during childhood and risk of type 1 diabetes mellitus
- Original Articles
- Glycemic variability predicts inflammation in adolescents with type 1 diabetes
- Prevalence and risk factors for diabetic retinopathy in a hospital-based population of Australian children and adolescents with type 1 diabetes
- One month of omega-3 fatty acid supplementation improves lipid profiles, glucose levels and blood pressure in overweight schoolchildren with metabolic syndrome
- The outcome of seven patients with hereditary tyrosinemia type 1
- Increased oxidative stress parameters in children with moderate iodine deficiency
- Relationship between 25(OH)D levels and circulating lipids in African American adolescents
- Endoglin and obestatin levels, cardiometabolic risk factors and subclinical atherosclerosis in children aged 10–18 years
- Lipoprotein-associated phospholipase A2 activity and low-density lipoprotein subfractions after a 2-year treatment with atorvastatin in adolescents with type 1 diabetes
- Genetic characteristics and long-term follow-up of 11 patients with congenital hyperinsulinism followed in a single center
- Pituitary volume in children with growth hormone deficiency, idiopathic short stature and controls
- Case Reports
- A novel insulin receptor mutation in an adolescent with acanthosis nigricans and hyperandrogenism
- Primary hyperparathyroidism may masquerade as rickets-osteomalacia in vitamin D replete children
- Co-existence of phenylketonuria either with maple syrup urine disease or Sandhoff disease in two patients from Iran: emphasizing the role of consanguinity
- Severe malnutrition causing superior mesenteric artery syndrome in an adolescent with Triple A syndrome
- Solving a case of allelic dropout in the GNPTAB gene: implications in the molecular diagnosis of mucolipidosis type III alpha/beta
