Abstract
Biallelic insulin receptor (INSR) gene mutations cause congenital syndromes of severe insulin resistance (SIR) known as Donohue syndrome (DS) and Rabson–Mendenhall syndrome (RMS). At presentation, DS and RMS are difficult to differentiate since they share many clinical features; however, while patients with DS usually die within 1 year of birth, individuals classified as RMS can reach adult age. INSR mutations can be also found in pubertal females with hyperinsulinism, hyperandrogenism, and acanthosis nigricans (type A SIR). We studied the INSR gene in five subjects with congenital SIR and in a patient with type A SIR. Nine biallelic INSR gene mutations (eight novels, including an in-frame deletion of INSR signal peptide) were identified in patients with congenital SIR; a heterozygous, spontaneous INSR mutation was detected in the patient with type A SIR. Two probands, presenting severe hirsutism at birth, died at the age of 3 months and were classified as DS, while other 2, currently 2 and 3 years old, were diagnosed with RMS (patients 3 and 4). The fifth patient with congenital SIR died when 14 months old. Nephrocalcinosis, hyperaldosteronism, hyperreninemia, and hypokalemia, in the absence of hypertension, were discovered in patients 3 and 5 when 24 and 4 months old, respectively. Patient 3, now 3 years/3 months old, still shows hyperreninemic hyperaldosteronism requiring potassium supplementation. We conclude that renal abnormalities resembling antenatal Bartter’s syndrome type II, recently reported also by others, is a common observation in patients with congenital SIR.
Similar content being viewed by others
References
Taylor SI, Cama A, Accili D, Barbetti F, Quon MJ et al (1992) Mutations in the insulin receptor gene. Endocr Rev 13:566–595
Semple RK, Savage DB, Cochran EK, Gorden P, O’Rahilly S (2011) Genetic syndromes of severe insulin resistance. Endocr Rev 32:498–514. doi:10.1210/er.2010-0020
Musso C, Cochran E, Moran SA, Skarulis MC, Oral EA et al (2004) Clinical course of genetic diseases of the insulin receptor (type A and Rabson–Mendenhall syndromes): a 30-year prospective. Medicine (Baltimore) 83:209–222
Barbetti F, Gejman PV, Taylor SI, Raben N, Cama A et al (1992) Detection of mutations in insulin receptor gene by denaturing gradient gel electrophoresis. Diabetes 41:408–415
Bhattacharyya I, Chehal HK (2011) White lesions. Otolaryngol Clin North Am 44:109–131. doi:10.1016/j.otc.2010.09.009
Wertheimer E, Barbetti F, Muggeo M, Roth J, Taylor SI (1994) Two mutations in a conserved structural motif in the insulin receptor inhibit normal folding and intracellular transport of the receptor. J Biol Chem 269:7587–7592
Longo N, Wang Y, Smith SA, Langley SD, DiMeglio LA et al (2002) Genotype–phenotype correlation in inherited severe insulin resistance. Hum Mol Genet 11:1465–1475
Moller DE, Cohen O, Yamaguchi Y, Assiz R, Grigorescu F et al (1994) Prevalence of mutations in the receptor gene in subjects with features of type A syndrome of insulin resistance. Diabetes 43:247–255
Rau H, Kocova M, O'Rahilly S, Whitehead JP (2000) Naturally occurring aminoacid substitutions at Arg1174 in the human insulin receptor result in differential effects on receptor biosynthesis and hybrid formation, leading to discordant clinical phenotypes. Diabetes 49:1264–1268
Carrasco de la Fuente M, Barrio Castellanos R, Alonso Blanco M, de la Calle Blasco H (2010) Long survival in Rabson–Mendenhall syndrome. Diabetes Res Clin Pract 89:e17–e18. doi:10.1016/j.diabres.2010.04.023
Liu M, Lara-Lemus R, Shu-ou S, Wright J, Haataja L, Barbetti F, Guo H, Larkin D, Arvan P (2012) Impaired cleavage of preproinsulin signal peptide linked to autosomal dominant diabetes. Diabetes 61:828–837. doi:10.2337/db11-0878
Elders JM, Schedewie HK, Olefsky J, Givens B, Char F et al (1982) Endocrine-metabolic relationships in patients with leprechaunism. J Natl Med Assoc 74:1195–1210
Unal S, Aycan Z, Halsall DJ, Kibar AE, Eker S et al (2009) Donohue syndrome in a neonate with homozygous deletion of exon 3 of the insulin receptor gene. J Pediatr Endocrinol Metab 22:669–674
Harris AM, Hall B, Kriss VM, Fowlkes JL, Kiessling SG (2007) Rabson–Mendenhall syndrome: medullary sponge kidney, a new component. Pediatr Nephrol 22:2141–2144
Abe Y, Sato T, Takagi M, Watanabe T, Nagayama Y et al (2012) A case of Rabson–Mendenhall syndrome with a novel mutation in the tyrosine kinase domain of the insulin receptor gene complicated by medullary sponge kidney. J Pediatr Endocrinol Metab 25:587–590
Chong YH, Taylor BJ, Wheeler BJ (2013) Renal manifestations of severe Rabson–Mendenhall syndrome: a case report. J Diabetes Metab Disord 12:7. doi:10.1186/2251-6581-12-7
Bhat YR, Vinayaka G, Sreelakshmi K (2012) Antenatal Bartter syndrome: a review. Int J Pediatr 2012:857136. doi:10.1155/2012/857136
Simon DB, Karet FE, Rodriguez-Soriano J, Hamdan JH, DiPietro A et al (1996) Genetic heterogeneity of Bartter’s syndrome revealed by mutations in the K+ channel, ROMK. Nat Genet 14:152–156
Hovnik T, Bratanic N, Trebusak Podkrajsek K, Kovac J, Paro D, et al (2012) Severe progressive obstructive cardiomyopathy and renal tubular dysfunction in Donohue syndrome with decreased insulin receptor autophosphorylation due to a novel INSR mutation. Eur J Pediatr published online 11 Dec 2012. doi:10.1007/s00431-012-1901-7
Vigneri R, Squatrito S, Sciacca L (2010) Insulin and its analogs: actions via insulin and IGF receptors. Acta Diabetol 47:271–278
Annunziata M, Granata R, Ghigo E (2011) The IGF system. Acta Diabetol 48:1–9
Semple RK, Williams R, Dunger DB (2010) What is the best management strategy for patients with severe insulin resistance ? Clin Endocrinol 73:286–290. doi:10.1111/j.1365-2265.2010.03810.x
Cochran E, Young JR, Sebring N, De Paoli A, Oral EA, Gorden P (2004) Efficacy of recombinant methionyl human leptin therapy for the extreme insulin resistance of the Rabson–Mendenhall syndrome. J Clin Endocrinol Metab 89:1548–1554
Hojlund K, Hansen T, Lajer M, Henriksen JE, Levin K et al (2004) A novel syndrome of autosomal-dominant hyperinsulinemic hypoglycemia linked to a mutation in the human insulin receptor gene. Diabetes 53:1592–1598
Huang Z, Li Y, Tang T, Xu W, Liao Z et al (2009) Hyperinsulinemic hypoglycaemia associated with a heterozygous missense mutation of R1174W in the insulin receptor gene. Clin Endocrinol 71:659–665. doi:10.1111/j.1365-2265.2009.03525.x
Acknowledgments
We thank the patients’ parents and relatives who participated in this study.
Conflict of interest
None.
Author information
Authors and Affiliations
Corresponding author
Additional information
Communicated by Antonio Secchi.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Grasso, V., Colombo, C., Favalli, V. et al. Six cases with severe insulin resistance (SIR) associated with mutations of insulin receptor: Is a Bartter-like syndrome a feature of congenital SIR?. Acta Diabetol 50, 951–957 (2013). https://doi.org/10.1007/s00592-013-0490-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00592-013-0490-x