Familial Hyperinsulinism due to HNF4A Deficiency and Benign Premature Adrenarche: A Case Report

Authors

  • Edward Compton BS, The Center for Endocrinology, Diabetes and Metabolism, Children’s Hospital Los Angeles, Los Angeles, CA, United States
  • David H. Geller MD, PhD, The Center for Endocrinology, Diabetes and Metabolism, Children’s Hospital Los Angeles, Los Angeles, CA, United States
  • Alaina P. Vidmar MD, The Center for Endocrinology, Diabetes and Metabolism, Children’s Hospital Los Angeles, Los Angeles, CA, United States https://orcid.org/0000-0003-3790-6255

DOI:

https://doi.org/10.5195/ijms.2021.721

Keywords:

Hyperinsulinism, Congenital hyperinsulinism, Adrenarche, HNF4A, Hyperandrogenism

Abstract

Background: Familial Hyperinsulinism due to HNF4A deficiency (FHI-HNF4A) is a form of diazoxide-sensitive, diffuse hyperinsulinism, characterized by transient or persistent hyperinsulinemic hypoglycemia, and a propensity to develop Maturity-Onset Diabetes of the Young type 1 (MODY1). The association between FHI-HNF4A deficiency and benign premature adrenarche (BPA) is unknown.

The Case: We report the case of a 5-year-old girl with FHI-HNF4A, controlled on diazoxide, who presented with BPA and Tanner stage III pubic hair associated with body odor and acne. Work-up revealed elevated dehydroepiandrosterone sulfate (DHEAS), elevated free testosterone, and advanced bone age. Insulin levels were elevated in the setting of normal fasting blood glucose. We discuss the possible hormonal underpinnings of hyperandrogenism.

Conclusion: Though the underlying pathophysiology of this phenotype is unclear, a possible synergistic mechanism exists between insulin-induced hyperandrogenism and HNF4A deficiency leading to a transient decrease of SHBG and thus increased free testosterone levels. Further investigation is required to determine the association between HNF4A dysfunction and BPA.

Metrics

Metrics Loading ...

References

Lord K, Dzata E, Snider KE, Gallagher PR, De Leon DD. Clinical Presentation and Management of Children with Diffuse Hyperinsulinism: A Review of 223 Cases. J Clin Endocrinol Metab. 2013; 98(11): E1786-E1789.

Ferrara C, Patel P, Becker S, Stanley CA, Kelly A. Biomarkers of Insulin for the Diagnosis of Hyperinsulinemic Hypoglycemia in Infants and Children. J Pediatr. 2016;168:212-9.

Aynsley-Green A, Hussain K, Hall J, et al. Practical management of hyperinsulinism in infancy. Arch Dis Child Fetal Neonatal Ed. 2000;82(2):F98-F107.

Flanagan SE, Kapoor RR, Mali G, et al. Diazoxide-responsive hyperinsulinemic hypoglycemia caused by HNF4A gene mutations. Eur J Endocrinol. 2010;162(5):987-92.

Kapoor RR, Locke J, Colclough K, et al. Persistent hyperinsulinemic hypoglycemia and maturity-onset diabetes of the young due to heterozygous HNF4A mutations. Diabetes. 2008;57(6):1659-63.

Lord K, De Leon DD. Monogenic hyperinsulinemic hypoglycemia: current insights into the pathogenesis and management. Int J Pediatr Endocrinol. 2013;3.

Odom DT, Zizlsperger N, Gordon DB, et al. Control of pancreas and liver gene expression by HNF transcription factors. Science. 2004;303(5662):1378-81.

Winters SJ, Gogineni J, Karegar M, et al. Sex hormone-binding globulin gene expression and insulin resistance. J Clin Endocrinol Metab. 2014;99(12):E2780-2788.

Utriainen P, Laakso S, Liimatta J, et al.. Premature adrenarche--a common condition with variable presentation. Horm Res Paediatr. 2015;83(4):221-31.

Kaya G, Yavas Abali Z, et al. Body mass index at the presentation of premature adrenarche is associated with components of metabolic syndrome at puberty. Eur J Pediatr. 2018 Nov;177(11):1593-601.

Ibáñez L, Potau N, Francois I, et al. Precocious pubarche, hyperinsulinism, and ovarian hyperandrogenism in girls: relation to reduced fetal growth. J Clin Endocrinol Metab. 1998 Oct;83(10):3558-62.

Ehrmann DA, Barnes RB, Rosenfield RL. Polycystic ovary syndrome as a form of functional ovarian hyperandrogenism due to dysregulation of androgen secretion. Endocr Rev. 1995 Jun;16(3):322-53.

Ibáñez L, Potau N, Zampolli M, et al. Hyperinsulinemia and decreased insulin-like growth factor-binding protein-1 are common features in prepubertal and pubertal girls with a history of premature pubarche. J Clin Endocrinol Metab. 1997 Jul;82(7):2283-8.

Ibáñez L, Potau N, Chacon P, et al. Hyperinsulinaemia, dyslipaemia and cardiovascular risk in girls with a history of premature pubarche. Diabetologia. 1998 Sep;41(9):1057-63.

Després JP, Lamarche B, Mauriège P, et al.. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med. 1996 Apr 11;334(15):952-7.

Snider KE, Becker S, Boyajian L, et al. Genotype and phenotype correlations in 417 children with congenital hyperinsulinism. J Clin Endocrinol Metab. 2013 Feb;98(2):E355-63.

Fruehwald-Schultes B, Kern W, Bong W, et al. Supraphysiological hyperinsulinemia acutely increases hypothalamic-pituitary-adrenal secretory activity in humans. J Clin Endocrinol Metab. 1999 Sep;84(9):3041-6.

Adashi EY, Hsueh AJ, Yen SS. Insulin enhancement of luteinizing hormone and follicle-stimulating hormone release by cultured pituitary cells. Endocrinology. 1981 Apr;108(4):1441-9.

Nestler JE, Powers LP, Matt DW, et al. A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome. J Clin Endocrinol Metab. 1991 Jan;72(1):83-9.

Nestler JE, Barlascini CO, Matt DW, Steingold KA, Plymate SR, Clore JN, Blackard WG. Suppression of serum insulin by diazoxide reduces serum testosterone levels in obese women with polycystic ovary syndrome. J Clin Endocrinol Metab. 1989 Jun;68(6):1027-32.

Rosenfield RL. Evidence that idiopathic functional adrenal hyperandrogenism is caused by dysregulation of adrenal steroidogenesis and that hyperinsulinemia may be involved. J Clin Endocrinol Metab. 1996;81(3):878-80.

Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med. 1996;335(9):617-23.

Ibanez L, Valls C, Potau N, et al. Sensitization to insulin in adolescent girls to normalize hirsutism, hyperandrogenism, oligomenorrhea, dyslipidemia, and hyperinsulinism after precocious pubarche. J Clin Endocrinol Metab. 2000;85(10):3526-30.

la Marca A, Morgante G, Paglia T, et al. Effects of metformin on adrenal steroidogenesis in women with polycystic ovary syndrome. Fertil Steril. 1999;72(6):985-9.

Hammond GL. Diverse roles for sex hormone-binding globulin in reproduction. Biol Reprod. 2011;85(3):431-41.

Winters SJ, Gogineni J, Karegar M, et al. Sex hormone-binding globulin gene expression and insulin resistance. J Clin Endocrinol Metab. 2014 Dec;99(12):E2780-8.

Downloads

Published

2021-05-17

How to Cite

Compton, E., Geller, D. H., & Vidmar, A. (2021). Familial Hyperinsulinism due to HNF4A Deficiency and Benign Premature Adrenarche: A Case Report. International Journal of Medical Students, 9(2), 167–170. https://doi.org/10.5195/ijms.2021.721

Issue

Vol. 9 No. 2 (2021)

Section

Case Report

Categories

License

  1. The Author retains copyright in the Work, where the term “Work” shall include all digital objects that may result in subsequent electronic publication or distribution.
  2. Upon acceptance of the Work, the author shall grant to the Publisher the right of first publication of the Work.
  3. The Author shall grant to the Publisher and its agents the nonexclusive perpetual right and license to publish, archive, and make accessible the Work in whole or in part in all forms of media now or hereafter known under a Creative Commons Attribution 4.0 International License or its equivalent, which, for the avoidance of doubt, allows others to copy, distribute, and transmit the Work under the following conditions:
    1. Attribution—other users must attribute the Work in the manner specified by the author as indicated on the journal Web site; with the understanding that the above condition can be waived with permission from the Author and that where the Work or any of its elements is in the public domain under applicable law, that status is in no way affected by the license.
    2. The Author is able to enter into separate, additional contractual arrangements for the nonexclusive distribution of the journal's published version of the Work (e.g., post it to an institutional repository or publish it in a book), as long as there is provided in the document an acknowledgment of its initial publication in this journal.
    3. Authors are permitted and encouraged to post online a prepublication manuscript (but not the Publisher’s final formatted PDF version of the Work) in institutional repositories or on their Websites prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work. Any such posting made before acceptance and publication of the Work shall be updated upon publication to include a reference to the Publisher-assigned DOI (Digital Object Identifier) and a link to the online abstract for the final published Work in the Journal.
    4. Upon Publisher’s request, the Author agrees to furnish promptly to Publisher, at the Author’s own expense, written evidence of the permissions, licenses, and consents for use of third-party material included within the Work, except as determined by Publisher to be covered by the principles of Fair Use.
    5. The Author represents and warrants that:
      1. the Work is the Author’s original work;
      2. the Author has not transferred, and will not transfer, exclusive rights in the Work to any third party;
      3. the Work is not pending review or under consideration by another publisher;
      4. the Work has not previously been published;
      5. the Work contains no misrepresentation or infringement of the Work or property of other authors or third parties; and
      6. the Work contains no libel, invasion of privacy, or other unlawful matter.
    6. The Author agrees to indemnify and hold Publisher harmless from the Author’s breach of the representations and warranties contained in Paragraph 6 above, as well as any claim or proceeding relating to Publisher’s use and publication of any content contained in the Work, including third-party content.

Enforcement of copyright

The IJMS takes the protection of copyright very seriously.

If the IJMS discovers that you have used its copyright materials in contravention of the license above, the IJMS may bring legal proceedings against you seeking reparation and an injunction to stop you using those materials. You could also be ordered to pay legal costs.

If you become aware of any use of the IJMS' copyright materials that contravenes or may contravene the license above, please report this by email to contact@ijms.org

 

Infringing material

If you become aware of any material on the website that you believe infringes your or any other person's copyright, please report this by email to contact@ijms.org