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

Title: ABSTRACT. 61 Background: Familial Hyperinsulinism due to HNF4A deficiency (FHI-HNF4A) is a form of diazoxide-sensitive, 63 diffuse hyperinsulinism, characterized by transient or persistent hyperinsulinemic hypoglycemia, and a 64 propensity to develop Maturity-Onset Diabetes of the Young type 1 (MODY1). The association between FHI- 65 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 68 BPA and Tanner stage III pubic hair associated with body odor and acne. Work-up revealed elevated 69 dehydroepiandrosterone sulfate (DHEAS), elevated free testosterone, and advanced bone age. Insulin levels 70 were elevated in the setting of normal fasting blood glucose. We discuss the possible hormonal underpinnings 71 of hyperandrogenism. Conclusion: Though the underlying pathophysiology of this phenotype is unclear, a possible synergistic 74 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 76 the association between HNF4A dysfunction and BPA.

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International Journal of Medical Students -Case report.

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Background: Familial Hyperinsulinism due to HNF4A deficiency (FHI-HNF4A) is a form of diazoxide-sensitive, 63 diffuse hyperinsulinism, characterized by transient or persistent hyperinsulinemic hypoglycemia, and a 64 propensity to develop Maturity-Onset Diabetes of the Young type 1 (MODY1). The association between FHI-65 HNF4A deficiency and benign premature adrenarche (BPA) is unknown.

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The Case: We report the case of a 5-year-old girl with FHI-HNF4A, controlled on diazoxide, who presented with 68 BPA and Tanner stage III pubic hair associated with body odor and acne. Work-up revealed elevated 69 dehydroepiandrosterone sulfate (DHEAS), elevated free testosterone, and advanced bone age. Insulin levels 70 were elevated in the setting of normal fasting blood glucose. We discuss the possible hormonal underpinnings 71 of hyperandrogenism.

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Conclusion: Though the underlying pathophysiology of this phenotype is unclear, a possible synergistic 74 mechanism exists between insulin-induced hyperandrogenism and HNF4A deficiency leading to a transient 75 decrease of SHBG and thus increased free testosterone levels. Further investigation is required to determine 76 the association between HNF4A dysfunction and BPA.

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Congenital hyperinsulinism (CHI) is due to a variety of etiologies that result in dysregulated insulin release from 83 pancreatic β-cells. There are two histological variants of CHI, focal and diffuse, which differ in the extent of 84 pancreatic involvement. In the diffuse variant, all of the β-cells are affected, while in the focal form, a localizable 85 lesion is found, affecting only a subset of the β-cells. 1     comedones, or accelerated growth velocity, are detected before the age of 8 in females or 9 in males, premature 103 adrenarche is present. 9 Prior studies have found increased rates of obesity in children with BPA. 9,10 However, 104 other conditions that present similarly must first be excluded before BPA can be diagnosed. These include: 105 central puberty, adrenocortical and gonadal sex-hormone secreting tumors, congenital adrenal hyperplasia, and 106 exposure to exogenous androgens. In some populations, BPA has been associated with low birth weight, insulin 107 resistance, adverse cardiometabolic risk, and progression to polycystic ovary syndrome (PCOS). 11-15 Herein, 108 we report a 5-year-old female patient with FHI-HNF4A who presented with BPA in the setting of elevated insulin 109 level, despite euglycemia on diazoxide therapy. The underlying pathophysiology of this phenotype remains 110 obscure; however, we discuss a possible synergistic mechanism between insulin-induced hyperandrogenism 111 and HNF4A deficiency, leading to transient decrease of SHBG and thus increased free testosterone levels.

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International Journal of Medical Students -Case report. 5 IJMS THE CASE.

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A 5-year-old girl with known FHI-HNF4A, who was first noted by her mother to have new-onset acne and body 115 odor without any associated breast changes, pubic hair, or menses at 4 years of age, presented to the pediatric 116 endocrinology clinic for follow-up. Her pubic hair had progressed to Tanner stage III with increased acne and 117 body odor. No exogenous steroid exposures were reported. Physical exam revealed Tanner stage 1 breasts.

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The patient's past medical history was significant for premature delivery at 34 weeks gestation due to premature

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The family was lost to follow up and presented for referral to the pediatric endocrinology clinic for consultation  it was recommended that blood glucose checks be increased to 6 times daily to ensure that cryptic hypoglycemia 151 was detected, as HbA1c was < 4.0%. She was placed on an iPro glucose monitor (CGM) to collect continuous 152 glucose levels for 96 hours, which demonstrated hypoglycemia 20% of the time. She was maintained on IJMS diazoxide at 12 mg/kg/day divided three times daily (TID). Due to concern for poor annualized growth velocity 154 of 1.4 cm/year, a bone age was obtained, which showed skeletal age concordant with chronological age.

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At a subsequent follow-up at 3.5 years old, her HbA1c was 4.0%, with weight gain and associated increased 157 annualized growth velocity of 6 cm/yr. Continuous glucose monitoring was recommended to detect overnight 158 hypoglycemic episodes, but the patient's family declined this option. She was receiving feeding therapy and her 159 oral intake had improved significantly. Although she no longer utilized G-tube feedings, she was having multiple 160 episodes of hypoglycemia overnight. Her diazoxide dose was increased to 13 mg/kg/day divided TID, with 161 resolution of her overnight hypoglycemia.

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International Journal of Medical Students -Case report. 7 IJMS DISCUSSION.

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We report a unique case of a 5-year-old female with FHI-HNF4A who presented with Tanner 3 pubic hair, acne, 165 body odor, elevated DHEAS and free testosterone, and advanced bone age in the absence of elevated estradiol 166 levels. Her presentation is most consistent with BPA; however, the relationship between FHI-HNF4A and BPA 167 remains poorly understood. Although the BMI percentile of our patient was 18%, prior studies have found an 168 association between BPA and obesity. 9,10 There is a wide differential diagnosis for patients that are found to be 169 persistently hypoglycemic after birth, including hyperinsulinism as in our patient, mutations in enzymes involved 170 in fatty acid metabolism, glycogen storage disorders, counter-regulatory hormone deficiencies.. While the 171 differential is broad, we suspected hyperinsulinemia as the culprit in our patient, given her father's diagnosis of

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found that females with BPA had higher body mass indexes and insulin concentrations. 10 These females also 207 had hyper-responsiveness to ACTH, leading to increased androstenedione and DHEA levels. This study further 208 elucidates the unique role insulin plays in the regulation of adrenal sex hormone production.

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An additional mechanism to consider in this patient is the effect of HNF4A function on SHBG levels. Hammond

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This case demonstrates that clinically silent hypoglycemia with concomitant intermittent hyperinsulinemia may 221 have long-term sequelae for the patient. Therefore, even if glycemic control is adequate overall, with HbA1c 222 levels within normal limits, it is important not to ignore either glucose levels or HbA1c levels that are down-

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We believe that our patient may have been experiencing episodes of hypoglycemia, as evidenced by her HbA1C