Congenital hyperinsulinism is a condition of dysregulated insulin secretion often caused by inactivating mutations of the ATP-sensitive K + (K ATP ) channel in the pancreatic β cell. Though most disease-causing mutations of the 2 genes encoding K ATP subunits, ABCC8 (SUR1) and KCNJ11 (Kir6.2), are recessively inherited, some cases of dominantly inherited inactivating mutations have been reported. To better understand the differences between dominantly and recessively inherited inactivating K ATP mutations, we have identified and characterized 16 families with 14 different dominantly inherited K ATP mutations, including a total of 33 affected individuals. The 16 probands presented with hypoglycemia at ages from birth to 3.3 years, and 15 of 16 were well controlled on diazoxide, a K ATP channel agonist. Of 29 adults with mutations, 14 were asymptomatic. In contrast to a previous report of increased diabetes risk in dominant K ATP hyperinsulinism, only 4 of 29 adults had diabetes. Unlike recessive mutations, dominantly inherited K ATP mutant subunits trafficked normally to the plasma membrane when expressed in COSm6 cells. Dominant mutations also resulted in different channel-gating defects, as dominant ABCC8 mutations diminished channel responses to magnesium adenosine diphosphate or diazoxide, while dominant KCNJ11 mutations impaired channel opening, even in the absence of nucleotides. These data highlight distinctive features of dominant K ATP hyperinsulinism relative to the more common and more severe recessive form, including retention of normal subunit trafficking, impaired channel activity, and a milder hypoglycemia phenotype that may escape detection in infancy and is often responsive to diazoxide medical therapy, without the need for surgical pancreatectomy.

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Extremely premature infants manifest clinical features suggestive of adrenal insufficiency. Yet, serum cortisol levels are similar in ill and well preterm infants in a setting where one would expect high stress levels in the ill infants. We investigated the hypothalamic-pituitary-adrenal axis in 17 extremely low birth weight stressed premature infants, mean birth weight 739 g, gestational age, 26.1 weeks, using ovine CRH (oCRH) and ACTH stimulation. oCRH (1 microgram/kg) was administered at 2-7 days of life (mean = 4.1). ACTH rose from a basal value 6.0 +/- 0.8 pmol/L (mean +/- SEM) to 9.6 +/- 1.8 pmol/L (P < 0.01) at 15 min and 9.5 +/- 1.7 pmol/L (P < 0.01) at 60 min. Basal cortisol rose from 349.3 +/- 58.1 nmol/L to 422.3 +/- 57.9 nmol/L (P < 0.01) at 15 min and 568.7 +/- 60.2 nmol/L (P < 0.01) at 60 min. Cortisol values remained significantly (P < 0.05) elevated 24 h after oCRH. An ACTH stimulation test performed 24 h after the oCRH test demonstrated a significant cortisol rise from 603.5 +/- 130.5 nmol/L to 882.7 +/- 136.6 nmol/L (P < 0.05) at 60 min. Plasma CRH immunoactivity was also measured before oCRH testing and was detectable in 10 of 15 infants. The mean CRH immunoactivity was 21.8 +/- 4.4 pmol/L in the infants, significantly higher than 8 adult male controls (P < 0.04). Our results show a normal pituitary response to ovine CRH and a normal adrenal response to ACTH. We hypothesize that cortisol levels are inappropriately low in some ill preterm infants because of the inability of the extremely premature brain to recognize the stress of the illness or because of inadequate hypothalamic secretion of CRH. The significance of the measurable plasma CRH in the first week of life is unknown.

Our objective was to determine if low levels of corticosteroid binding globulin (CBG) might explain the low serum total cortisol levels found in some extremely low-birth-weight (ELBW) infants. In a prospective study, serum total cortisol and CBG were measured in single blood samples from 31 ELBW infants, with a gestational age less than 28 weeks, in the first 8 days of life. Severity of illness was assessed using the Score for Neonatal Acute Physiology Perinatal Extension (SNAP-PE). The mean serum total cortisol (mean +/- 1 SD) was 9.2 +/- 9.8 mcg/mL and the mean CBG level was 1.4 +/- 0.31 mg/dL. There was no significant correlation between serum total cortisol and CBG levels (r = -0.18), severity of illness as measured by the SNAP-PE (r = +0.12), or birth weight (r = -0.12). Five of 31 infants, having a mean SNAP-PE score of 41, had serum total cortisol levels < or = 3.0 mcg/dL. Estimated mean serum free cortisol concentrations in these five infants (0.76 mcg/dL) were comparable to estimated free cortisol levels diagnostic of adrenal insufficiency in sick adult patients. Our findings indicate that CBG levels are lower in ELBW infants than in term infants, but low CBG levels do not explain the low serum total cortisol levels found in some very sick infants. Low cortisol levels in small premature infants may be adequate to support growth if the infant is well, but may result in a syndrome of adrenal insufficiency in those with severe illnesses.