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.

We present a case of pelvic venous congestion in a 13-year-old girl who complained of pelvic pain for 9 months. The diagnosis of pelvic congestion syndrome was suggested by imaging modalities, including sonography, CT and MRI, with classically described imaging findings. The girl underwent diagnostic laparoscopy, where visual inspection demonstrated congested pelvic veins and endometriosis. After removal of endometrial implants, the child's pain persisted and she subsequently underwent venography and embolization of the ovarian veins. We found no literature describing pelvic venous congestion (PVC) in children. Knowledge that PVC exists in children is important, particularly for pediatric radiologists who are imaging patients with complaints of pelvic pain

Background: Serum anti-Mullerian hormone (AMH) levels are frequently elevated in patients with Polycystic Ovarian Syndrome (PCOS) due to increased production by granulosa cells in high numbers of preantral and antral follicles. Ovarian volume is often high in PCOS due to increased follicle number and elevated stromal mass. Little is known about the relationship between serum AMH and ovarian ultrasound (US) features in adolescents with PCOS.Objectives:To compare serum AMH levels in obese adolescent girls with PCOS and obese controls. To correlate serum AMH levels in the PCOS group with ovarian US features. To correlate serum AMH levels with body mass index (BMI) z-score, severity of hyperandrogenism, and degree of insulin resistance. Methods:We performed a cross-sectional retrospective analysis of clinical and biochemical findings in 23 obese adolescent females with PCOS (mean BMI z-score 2, mean age 15.2 yrs) and 12 obese age and sex matched controls (mean BMI z-score 2, mean age 14.1 years). All subjects were post-menarcheal. Serum AMH levels were assessed via ELISA and compared between groups. In the PCOS group, transabdominal ovarian US were reviewed for follicular distribution (peripheral, central, or mixed), number, and ovarian volume. AMH levels were correlated with ovarian US findings, BMI z-score, androgen levels, and fasting insulin levels. Results:Mean free testosterone was 9.76 +-5.13 pg/mL in the PCOS group versus 5 +-2.02 pg/mL in controls (p=0.0092). Both groups were comparable in fasting insulin and glucose. Serum AMH was 6.78 +-3.55 ng/mL in the PCOS group versus 3.38 +-1.48 ng/mL in controls (p=0.0004). AMH positively correlated with ovarian volume (left ovary p=0.0007, right ovary p=0.0065) and peripheral follicle distribution (p=0.0027). Ten or more follicles were observed in 83% of US. No significant correlation existed between AMH and BMI z-score, free testosterone, or fasting insulin. Conclusions: This study is the first to demonstrate a positive relationship between serum AMH levels and ovarian volume in adolescents with PCOS. Our findings support the use of serum AMH as a reflection of ovarian volume in cases where accurate ultrasounds are not available as well as for follow up. By potentially influencing ovarian volume, AMH may impact stromal mass which is mainly theca cell dependent. These results thereby lend support to the existence of AMH mediated crosstalk between granulosa and theca cells

Background: Patients with Polycystic Ovarian Syndrome (PCOS) often suffer from co-morbidities associated with chronic inflammation characterized by elevations in pro-inflammatory cytokines. There is limited data on markers of chronic inflammation in adolescents with PCOS.Objectives:To compare serum levels of IL-1alpha, IL-6, IL-18, and TNF-alpha in obese adolescents with PCOS and obese controls. In the PCOS group, to correlate cytokine levels with ovarian ultrasound (US) features. To correlate cytokine levels with body mass index (BMI) z-score, severity of hyperandrogenism, and degree of insulin resistance. Methods:We performed a cross-sectional retrospective analysis of clinical and biochemical findings in 23 obese adolescent females with PCOS (mean BMI z-score 2, mean age 15.2 yrs) and 12 obese age and sex matched controls (mean BMI z-score 2, mean age 14.1 years). All subjects were post-menarcheal. Serum IL-1alpha, IL-6, IL-18, and TNF-alpha levels were compared between groups. In the PCOS group, cytokine levels were correlated with ovarian US features, BMI z-score, androgen levels, and fasting insulin and glucose levels. Results: Mean free testosterone was 9.76 +-5.13 pg/mL in the PCOS group versus 5 +-2.02 pg/mL in the control group (p=0.0092). Both groups were comparable in fasting glucose and insulin. TNFalpha was 7.4 +- 4 pg/mL in the PCOS group versus 4.8 +- 2.8 pg/mL in the control group (p<0.05). There was no significant correlation between TNFalpha and BMI z-score, free testosterone, fasting insulin, or fasting glucose. No correlation existed between TNFalpha and ovarian follicle number, distribution, or volume. In both groups, the majority of the results were below the lower limit of detectability of the assays for serum IL-1alpha and IL-6. There was no significant difference in IL-18 between groups (p=0.2). Conclusions:Serum TNFalpha levels are elevated in adolescents with PCOS in patients as young as 12 years. Chronic TNFalpha elevation is known to contribute to increased acute phase protein release, subendocardial inflammation, atherosclerosis, and insulin resistance. Early identification and treatment of adolescents with PCOS is important to prevent future complications associated with a chronic pro-inflammatory state

Background: Congenital adrenal hyperplasia due to 11-beta hydroxylase is a rare genetic disorder. It is transmitted as an autosomal recessive trait. We describe a novel genetic mutations, in a 19 year old untreated male with 11-Beta hydroxylase deficiency, severe CAH with late presentation and TART. Methods: A 19 years old Chinese male presented with testicular masses, hypertension and hypokalemia. Hormonal studies showed elevated 17-hydroxyprogesterone, androstenedione, DOC, ACTH and markedly elevated 11-deoxycortisol levels, low cortisol, aldosterone and plasma renin activity levels. Ultrasonographic imaging revealed markedly abnormal appearing testes, with diffuse hypervascularity and numerous confluent infiltrative nodules, suggestive of TART. Genetic analysis revealed novel R43Q in Exon1, A386V in Exon7 and G452V in Exon8 mutations on chromosome 8. Results: Normalization of ACTH, reduction in 11-deoxycortisol, DOC and additional metabolites were achieved with steroid treatment.Conclusion: This is a 19 yo male from China with CAH secondary to 11-beta hydroxylase who was found to have novel mutations

The rates of type 2 diabetes (T2DM) continue to parallel the rising rates of obesity in the United States, increasingly affecting adolescents as well as adults. Hippocampal and frontal lobe reductions have been found in older adults with type 2 diabetes, and we sought to ascertain if these brain alterations were also present in obese adolescents with T2DM. In a cross-sectional study we compared MRI-based regional brain volumes of 18 obese adolescents with T2DM and 18 obese controls without evidence of marked insulin resistance. Groups were matched on age, sex, school grade, ethnicity, socioeconomic status, body mass index, and waist circumference. Relative to obese controls, adolescents with T2DM had significantly reduced hippocampal and prefrontal volumes, and higher rates of global cerebral atrophy. Hemoglobin A1c, an index of long-term glycemic control, was inversely associated with prefrontal volume and positively associated with global cerebral atrophy (both p < 0.05). Brain integrity is negatively impacted by T2DM already during adolescence, long before the onset of overt macrovascular disease. Paralleling the findings of greater vascular and renal complications among obese adolescents with severe insulin resistance and T2DM relative to their age-matched peers with type 1 diabetes, we find clear evidence of possible brain complications. Our findings call for aggressive and early intervention to limit the negative impact of obesity-associated insulin resistance leading to T2DM on the developing brains of adolescents.

OBJECTIVES: To study the age at diagnosis of polycystic ovarian syndrome (PCOS) in a pediatric population. To compare risk factors involved in causing PCOS in preadolescent and adolescent girls. To review the current literature on the reported age of PCOS in girls. DESIGN: A retrospective chart review and systematic review of the literature. PARTICIPANTS: Patients included 58 girls (age </=18 yrs) with a diagnosis of PCOS based on the Rotterdam criteria. Girls were grouped as preadolescents (<13 yrs) or adolescents (13-18 yrs). Clinical and biochemical data were reviewed from the time of diagnosis. MAIN OUTCOME MEASURES: Age at diagnosis. Differences in risk factors for PCOS (Ethnicity, obesity, family history of PCOS, birth weight, age at pubarche, thelarche and menarche, evidence of hyperandrogenism and/or insulin resistance) were compared between the two groups. RESULTS: There were 26% (15/58) preadolescent girls (9-12 yrs) vs 74% (43/58) adolescents (13-18 yrs). There was no significant difference between the two groups in ethnicity, BMI z-score, family history of maternal PCOS, birth weight, hyperandrogenism, or insulin resistance. Preadolescents with PCOS had significantly earlier onset of pubarche and thelarche than adolescents with PCOS, by 1.9 and 1.5 yrs, respectively (P = 0.018, 0.030). In addition to earlier puberty, PCOS developed 2.1 years sooner after thelarche in preadolescents than in adolescents. (P = 0.008) Preadolescents were significantly taller for age than adolescents (72nd % vs 43rd %) (P = 0.005). A review of the 28 studies published in the last 3 years that included PCOS patients with age <=18 yrs described only 6.4% (27/425) of pediatric subjects with age <13 yrs. Four were primarily pediatric studies that included patients under the age of 13 yrs, with 9.4% (12/127) of the patients <13 yrs. CONCLUSION: Increased awareness of PCOS in young females is needed. PCOS may occur at a younger age in girls who develop early pubarche and thelarche. Therefore, the diagnosis and workup should be considered in young girls with risk factors suggestive of PCOS

OBJECTIVE: Our aim was to evaluate uterine and ovarian ultrasonographic features including endometrial thickness (ET) in adolescent females with PCOS, which is limited in this population. METHODS: We performed a retrospective chart review of young females (n=51) ranging in age from 10 to 18 years with the diagnosis of PCOS. Clinical, biochemical and pelvic sonography data were reviewed. Sonographic data included uterine parameters of ET, length, and volume as well as ovarian volume and follicular morphologic features. RESULTS: Data in 51 girls were analyzed. Menstrual periods were reported as irregular in 26/51 (50.9%), amenorrheic in 19/51 (37.2%), regular in 4/51 (7.8%) and metrorrhagia in 2/51 (3.9%). Uterine features revealed that the endometrial stripe was enlarged (>7mm) in 16/51 (31.4%) of girls, all with homogeneous appearance. The uterine length was lower than normal in 22/51 (43.1%) of girls, normal in 21/51 (41.2%), and higher than normal in 8/51 (15.7%). Uterine volume was normal in 31/51 (60.7%) and higher in 20/51 (39.3%) of girls. Enlarged ovarian volume was found in 22/51 (43%) of patients. Mean ovarian volumes were 16.1cm(3) and 13.1cm(3) in bilateral and unilaterally enlarged ovaries, respectively. The morphology of ovarian follicles was studied in a subset of 40 patients. The location of ovarian follicles was peripheral in 81% and mixed in 19%. The number of follicles was also examined in 43 patients. They were few (<5) in 12%, moderate (5-10) in 5% and multiple (>10) in 84% cases. There was the presence of at least one >10mm cyst in 25% of girls. CONCLUSION: Majority of the adolescents with PCOS demonstrated multiple peripheral ovarian follicles, with large ovarian volumes in some, indicating an important role of ultrasonography in the diagnosis of PCOS, even at a younger age. Endometrial thickness, uterine length, ovarian size, and follicular morphology should be carefully examined in cases of adolescent PCOS

AIMS: To evaluate clinical, biochemical and radiological features in adolescent females with unilateral polycystic ovary (UniPCO) versus bilateral polycystic ovary (BiPCO) in patients with polycystic ovarian syndrome (PCOS), and to compare the association of insulin resistance (IR) and metabolic syndrome (MS) between the two groups. SETTING: Pediatric endocrine clinic. METHODS: A retrospective chart review of girls with the diagnosis of PCOS was performed. They were divided into two groups: PCOS with UniPCO and BiPCO. RESULTS: No difference was seen between the two groups in regard to clinical parameters. LH/FSH ratio was significantly higher in patients with BiPCO. No difference was seen in free testosterone, lipids, MS or IR between groups. Ultrasound showed a mean ovarian volume of 13.2 +/- 1.5 ml on the affected side in UniPCO and 16.1 +/- 1.2 ml in BiPCO. Ovarian follicle location was mostly peripheral in both UniPCO and BiPCO. Multiple follicles were found in the majority of cases. IR and MS were present in 40% of girls with UniPCO and 38% and 23%, respectively, in girls with BiPCO. CONCLUSION: UniPCO may be a forerunner of BiPCO and may represent an early point along the continuum. Later, the unaffected ovary continues to increase in volume, resulting in BiPCO. Metabolic abnormalities of patients with UniPCO highlights that as well as being a precursor of BiPCO, it also imparts considerable health risks

Thyrotropinomas tend to be aggressive, invasive tumors that are difficult to resect because of their marked fibrosis and their proximity to vital structures such as the optic chiasm. The latter characteristic also limits the use of radiation therapy. In the few cases reported of children younger than 18 years whose thyrotropinomas were treated surgically, the results were disappointing. We present here the case of a 16-year-old boy with a thyrotropin-secreting pituitary macroadenoma who underwent partial resection via a transsphenoidal approach and was left with significant residual tumor and continued hyperthyroidism. He subsequently received 4 years of long-acting release somatostatin therapy, during which he has remained euthyroid without requiring antithyroid medication. To our knowledge, this is thus far the longest duration of somatostatin therapy in the pediatric age group. This regimen also achieved a decrease in compression of the optic nerve and prevented further tumor growth. We review here the current literature on somatostatin analog treatment including molecular mechanisms and promising new treatment modalities, such as the heterodimerization of dopamine and somatostatin receptors. We conclude that this has been a useful adjuvant treatment for our adolescent patient