Faculty Bibliography

BACKGROUND: Activating mutations of the ABCC8 gene can lead to permanent neonatal diabetes mellitus (PNDM). Glucose variability in infants with NDM treated with insulin can be extreme. We report long-term glycemic control in a patient with PNDM on sulfonylurea therapy, despite initial allergic reaction. METHODS: A Chinese girl presented on the first day of life with persistent hyperglycemia. Despite treatment with various insulin regimens, hemoglobin (Hb)A1c (normal 4.8%-6.3%) increased from 5.0% at 14 days of age to a peak of 9.7% at 15 months of age. Her average insulin dose was 0.5 units/kg/day. Genetic analysis revealed two novel ABCC8 gene activating mutations encoding the beta-cell sulfonylurea-1 receptor of the ATP-sensitive potassium channel. At age 3 years 2 months, transition from insulin to the oral sulfonylurea glyburide was initiated. After 8 days, she developed urticaria, palmar erythema, and a diffuse maculopapular rash, which resolved when medication was discontinued. At age 3 years 11 months, glyburide was reintroduced at a very low dose and was increased with concomitant weaning of insulin over the following 6 months. RESULTS: Normoglycemia (HbA1c 5.6%) was achieved on glyburide without any further allergic reaction at the age of 4 years 5 months with improved metabolic control. For the next 3 years, HbA1c measurements, and glucose means and variability were significantly lower compared with values during insulin therapy. CONCLUSIONS: As compared with subcutaneous insulin, oral sulfonylureas improved long-term metabolic control in a patient with NDM caused by novel activating mutations in the ABCC8 gene. Desensitization permitted safe oral sulfonylurea therapy in our patient with NDM despite initial allergic reaction. Fewer episodes of hypoglycemia occurred on sulfonylurea than on insulin therapy, which is an advantage in a very young child.

Background: Contiguous gene deletion of the Wilms tumor gene (WT1) is associated with two well described syndromes; Denys-Drash (DDS) and Frasier (FS). Both are associated with nephropathy and ambiguous genitalia and have overlapping clinical and molecular features (1). The known risk of Wilms tumors in DDS and gonadoblastomas in FS patients requires tumor surveillance.Case report: We evaluated a newborn with ambiguous genitalia, intact Mullerian structures (uterus) and small bilateral perivesicular gonads with a 46,XY (SRY+) karyotype. The physical exam revealed labia with clitoromegaly (1.2 cm in length). There were separate uretheral and vaginal openings with no urogenital sinus. Labs in the early neonatal period (Quest Diagnostics: all male references) revealed 17-OH-Progesterone 96 (<420 ng/dL), testosterone 133 (2-23 ng/dL; tanner 1), DHEAS 441 (73-367 ug/dL), inhibin A <1 (<21 pg/mL; prepubertal), inhibin B 35 (<161 pg/mL; 3-9 years old), and AMH 3.7 (87.3-243 ng/mL; 1-6 years old). After a joint discussion with the family, geneticist, endocrinologist, and psychologist the infant was assigned a female gender. Based on the phenotype (ambiguous genitalia, pre and postnatal hydronephrosis, and genitourinary abnormalities), the exon and exon-intron boundaries were sequenced. A missense mutation leading to the substitution of lysine for glutamine at position 369 of the WT1 protein (Q369K) in exon 8 was found to be consistent with Denys-Drash syndrome. At seven months of age the patient underwent a clitoroplasty and gonadectomy. Bilateral gonadoblastomas were found in an indeterminate left gonad and a right testis. In addition, the patient had bilateral grade 2-3 vesicoureteral reflux and progressed to end stage renal failure at 11 months of age (creatinine 1.4mg/dl). Consequently, the patient has secondary hyperparathyroidism with PTH 691 (12-65 pg/mL), calcium 7.2 (8-10.4 mg/dL), and phosphorus 7 (2.7-4.5 mg/dL). The patient's most recent renal ultrasound does not show evidence of a Wilms tumor (2).Conclusion: This is one of the earliest cases of bilateral gonadoblastoma reported in DDS. This case highlights the importance of early gonadectomy at the time of diagnosis of the WT1 gene mutation as these tumors have potential for malignant transformation

Background: ALL maintenance therapy (MT) has been occasionally associated with symptomatic hypoglycemia (SH) [1], attributed to purine analogue (mercaptopurine; 6-MP).[2] 6-MP has been hypothesized to affect substrate utilization of gluconeogenic precursor alanine in the liver.[3] Even though thousands of children in the US are currently on 6-MP, the actual prevalence rate of 6-MP induced hypoglycemia has not been reported.Case report: 5 year overweight (weight 67^th percentile, BMI 90^th percentile for his age) male with ALL was evaluated for SH (lethargy and vomiting) which occurred 8-10 hours after fasting while receiving daily 6-MP. Hypoglycemic episodes (capillary blood glucose levels (BGs) were 35-65mg/dL), >20 episodes/ month, occurred predominantly around mid morning, but not during the 5-day dexamethasone pulse. Cortrosyn test yielded a normal cortisol response (0 min: 13 and 60 min: 25.9mug/dL) which ruled out pituitary adrenal suppression. A 12 hour overnight fasting glucose was 49 mg/dL, with suppressed insulin response < 2 muIU/mL, low C-peptide of 0.5ng/mL (0.8-3.5ng/mL), high IGF BP1 >160ng/mL (20-105ng/mL), high free fatty acid 2.64mmol/L (0.5-0.9mmol/L) and negative glucagon stimulation test ({Delta} BG <5mg/dL). These results ruled out hyperinsulinism and the diagnosis of ketotic hypoglycemia was made. The patient was placed on cornstarch therapy 5 hours prior to dose of 6-MP. This treatment reduced the SH events to <2 episodes/month. To study the efficacy of cornstarch, patient was placed on iPro professional CGM (Medtronic Diabetes) with a preset low alarm at 70mg/dL, was worn for a period of 5 days while patient was on cornstarch. With 1000 sensor readings the BG range was 65-158mg/dL. Mean absolute difference (MAD%) between sensor and finger stick BG readings (parent monitored patient's BG 4 times/day) was 9.4%. There was only one episode of asymptomatic hypoglycemia down to 65 mg/dL detected in the CGM.Conclusion: CGM technology helped us devise an effective management plan for our patient. CGM proved useful as an adjunct to characterize the pattern of hypoglycemia and validate the benefit of cornstarch in hypoglycemia associated with 6MP treatment of ALL

BACKGROUND: The optimal dose and efficacy of (1)(3)(1)I treatment of children and adolescents with well-differentiated thyroid carcinoma (WDTC) and pulmonary metastases are not well established. A therapeutic challenge is to achieve the maximum benefit of (1)(3)(1)I to decrease disease-related morbidity and obtain disease-free survival while avoiding the potential complications of (1)(3)(1)I therapy. SUMMARY: We systematically reviewed the published literature on children and adolescents with WDTC and pulmonary metastases treated with (1)(3)(1)I to examine outcomes after (1)(3)(1)I administration and the risks and benefits of therapy. After reviewing 14 published articles, 9 articles met our inclusion criteria encompassing 112 pediatric and adolescent patients with WDTC and pulmonary metastases 21 years of age or younger at diagnosis spanning a follow-up period of 0.6-45 years. (1)(3)(1)I therapy after surgery and thyrotropin suppression resulted in complete, partial, and no disease response in 47.32%, 38.39%, and 14.29% of patients, respectively. Five studies provided data on disease response in relation to (1)(3)(1)I dose. In general, nonresponders received the highest (1)(3)(1)I doses and complete responders received a higher dose than partial responders. The disease-specific mortality rate was 2.68%. Survival was 97.32%. A second primary malignancy occurred in one patient. One out of 11 patients studied experienced radiation fibrosis. CONCLUSIONS: This review confirms that the majority of pediatric and adolescent patients with WDTC and pulmonary metastases treated with (1)(3)(1)I do not achieve complete response to therapy, yet disease-specific morbidity and mortality appear to remain low. It is therefore prudent to use caution in the repeated administration of (1)(3)(1)I to such patients to ensure that adverse effects of therapy do not cause more harm than good in a disease that has an overall favorable natural course. Long-term prospective studies are needed to analyze disease-specific morbidity and mortality, recurrence rate, dose-specific response, and dose-related adverse effects of (1)(3)(1)I in this patient population

Pituitary apoplexy is an acute clinical event usually caused by hemorrhage or infarction in a pituitary adenoma. We report the unusual case of hemorrhagic pituitary apoplexy in an 18 year-old male with previously undiagnosed type 2 diabetes mellitus who presented with unexplained hyperglycemia (glucose 49.2 mmol/l [887 mg/dl]) and obtundation and in whom an initial diagnosis of non-ketotic hyperglycemic coma (NKHC) was made. MRI revealed a heterogeneous mass arising from an expanded sella turcica into the suprasellar cistern. Despite well-controlled glucose levels on continuous insulin infusion, dexamethasone, and initiation of bromoergocriptine (parlodel) therapy, the patient's vision and pupillary responses deteriorated acutely. Following emergency transphenoidal surgery, the patient's vision and mental status improved. Data confirmed preoperative panhypopituitarism; serum prolactin was 396 ng/ml (microg/l). Immunostudies demonstrated tumoral labeling for prolactin, but not for ACTH, GH, TSH, LH, FSH, or P53

Diabetes mellitus is a frequent transient or rare permanent complication of pregnancy. The role of autoimmune phenomena in this gestational form of diabetes is incompletely understood. We have examined sera from 312 pregnant women who had abnormal glucose tolerance (based on a screening examination during the second trimester) for the presence of islet cell surface antibodies or insulin autoantibodies. Fifty-eight of these women were lost to follow-up. Of the remaining subjects, 144 (57.1%) had gestational diabetes diagnosed by formal glucose tolerance testing and the others (42.9%) were normal. Sixty percent of the women with gestational diabetes eventually required insulin to control their blood glucose during pregnancy. One serum from the non-diabetic women was positive for insulin antibodies (0.9%); 8 of the sera from the patients with gestational diabetes were positive (5.6%). Subsequent analysis revealed that all nine of the women whose sera were positive for insulin autoantibodies had been treated with insulin previously. Islet cell surface antibodies were strongly correlated with gestational diabetes. Forty-five of 144 gestational diabetic sera were positive (31.3%) whereas only 9 of 108 suspect control sera (8.3%) and 7 of 60 unknown sera (11.7%) were positive. These data suggest that a high percentage of pregnant women who screen positive for glucose intolerance have serological evidence of an autoimmune response against the pancreatic islets, in spite of the state of relative immune tolerance during pregnancy. These data suggest that autoimmune phenomena may play a role in gestational diabetes and that the presence of islet cell antibodies can predict insulin-requiring gestational diabetes.

The effect of the stress of crowded housing conditions (10 mice/cage) on the onset of diabetes after multiple, sub-diabetogenic doses of streptozotocin (MSZ) in male C57BL/KsJ mice was investigated. Prior to MSZ treatment, the group-housed and individually-housed animals had similar plasma glucose levels, while the former group's plasma corticosterone (CS) levels were elevated (54 +/- 8 ng/ml, p less than 0.03; 166% of the latter group). The group-housed animals became hyperglycemic (253 +/- 23 mg/dl) 2 days after the MSZ (day 7), with maximum hyperglycemia (506 +/- 23 mg/dl) developing by day 10. The individually housed animals did not become hyperglycemic until day 10 (303 +/- 24 mg/dl, p less than 0.001), and did not reach maximal hyperglycemia until between days 31 and 46, when plasma glucose levels were no longer different from the group-housed mice (507 +/- 37 mg/dl). There was a significant and progressive rise in CS levels of the stressed animals, reaching 218 +/- 25 ng/ml at day 46. The rise in CS of the unstressed animals was not significant until day 46, when the mean value reached 96 +/- 19 ng/ml (p less than 0.001 vs. basal). However, even at the conclusion of the experiment, the mean CS in the stressed animals was still 227% of that in the unstressed group (p less than 0.001). These studies demonstrate that the effects of stress (biochemically documented as an increase in CS levels) act synergistically with streptozotocin to promote an earlier onset of diabetes mellitus in males of this murine strain.