A case of novel mutation in ANOS1 (KAL1) gene and review of Kallmann syndrome.

Summary: Kallmann syndrome (KS) is a genetically heterogeneous condition characterized by hypogonadotropic hypogonadism with coexisting anosmia or hyposmia along with potential other phenotypic abnormalities depending on the specific genetic mutation involved. Several genetic mutations have been described to cause KS. The ANOS1 (KAL1) gene is responsible for 8% of mutations causing KS. A 17-year-old male presented to our clinic with delayed puberty and hyposmia, along with a family history suggestive of hypogonadism in his maternal uncle. Genetic testing for KS revealed complete exon 3 deletion in the ANOS1 gene. To the best of our knowledge, this specific mutation has not been previously described in the literature. Learning points: Missense and frameshift mutations in the KAL1 or ANOS1 gene located in the X chromosome are responsible for 8% of all known genetic mutations of Kallmann syndrome. Exon 3 deletion is one of the ANOS1 gene is a novel mutation, not reported before. Targeted gene sequencing for hypogonadotropic hypogonadism can be employed based on the phenotypic presentation.

Increased Rates of Hospitalized Children with Type 1 and Type 2 Diabetes Mellitus in Central Brooklyn during the COVID-19 Pandemic.

Following reports of increased new-onset diabetes and worse severity of DKA for children with diabetes following SARS-CoV-2 infection, we studied hospitalization rates for children with type 1 diabetes (T1DM) and type 2 diabetes (T2DM) in our center during the citywide shutdown. Methods. We conducted a retrospective chart review of children admitted to our two hospitals from January 1, 2018, to December 31, 2020. We included ICD-10 codes for diabetic ketoacidosis (DKA), hyperglycemic hyperosmolar syndrome (HHS), and hyperglycemia only. Results. We included 132 patients with 214 hospitalizations: 157 T1DM, 41 T2DM, and 16 others (14 steroid induced, 2 MODY). Overall admissions rates for patients with all types of diabetes were 3.08% in 2018 to 3.54% in 2019 (p = 0.0120) and 4.73% in 2020 (p = 0.0772). Although there was no increase of T1DM admissions across all 3 years, T2DM admission rates increased from 0.29% to 1.47% (p = 0.0056). Newly diagnosed T1DM rates increased from 0.34% in 2018 to 1.28% (p = 0.002) in 2020, and new-onset T2DM rates also increased from 0.14% in 2018 to 0.9% in 2020 (p = 0.0012). Rates of new-onset diabetes presenting with DKA increased from 0.24% in 2018 to 0.96% in 2020 (p = 0.0014). HHS increased from 0.1% in 2018 to 0.45% in 2020 (p = 0.044). The severity of DKA in newly diagnosed was unaffected (p = 0.1582). Only 3 patients tested positive for SARS-CoV-2 infection by PCR. Conclusion. Our urban medical center is located in Central Brooklyn and serves a majority who are Black. This is the first study investigating pediatric diabetes cases admitted to Brooklyn during the first wave of the pandemic. Despite the overall pediatric admissions declining in 2020 due to the citywide shutdown, overall hospitalization rates in children with T2DM and in new-onset T1DM and T2DM increased, which is not directly associated with active SARS-CoV-2 infection. More studies are needed to elucidate the reason for this observed increase in hospitalization rates.

Assessment of Microvascular Function in Children and Adolescents with Diabetes and Obesity.

BACKGROUND: Endothelial dysfunction (ED) is a marker of vascular damage. Glycated hemoglobin (A1C) predicts vascular complications. The EndoPAT (peripheral arterial tonometry) device calculates the reactive hyperemic index (RHI), a measure of endothelial function. The greater the vasodilation, the higher the RHI. We hypothesized that children with poorly-controlled diabetes mellitus (DM) and non-diabetes mellitus (NDM) obese children have ED. METHODS: A cross-sectional study using the EndoPAT device was performed on children with poorly-controlled DM and NDM children. ANOVA, t-test, Mann-Whitney U test, multiple linear regression and Spearman correlation were used. RESULTS: Of 58 children that completed the study (aged 13.1 ± 3.42 years), 33 with type 1 diabetes (T1DM), 8 with type 2 diabetes (T2DM) and 17 were NDM obese children. Eighty-five percent were African-American, 60% were female and 79% entered puberty. The RHI of children with DM (1.42 ± 0.48) versus NDM obese group (1.40 ± 0.34) was not different (P = 0.86) regardless of the type of DM or body mass index. In the DM group, for every 1% increase in latest A1C, the RHI decreased by 0.097 (P = 0.01) after adjusting for age, gender, and type of DM. The RHI of DM patients with latest A1C of < 10% (1.70 ± 0.58) versus those with A1C ≥10% (1.21 ± 0.19) was statistically different (P = 0.02). In the total study population, males had significantly lower RHI (1.28 ± 0.36) when compared to females (1.51 ± 0.46), P = 0.04 but this difference disappeared when considering pubertal status and type of diabetes. CONCLUSIONS: Our data showed that patients with poorly-controlled DM as reflected by latest A1C of ≥ 10% had worse endothelial function as reflected by lower RHI score.

Kidney function in minority children and adolescents with metabolically healthy and unhealthy obesity.

Metabolic syndrome and/or body mass index (BMI) ≥40 kg/m2 are risk factors for kidney function decline in the general population. To compare creatinine (Cr), estimated glomerular filtration rate (eGFR) and blood urea nitrogen (BUN) between minority children and adolescents with metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO), a chart review was conducted on subjects aged 4 to 20 years with BMI ≥95th percentile from July 2014 to April 2017. They were stratified into MHO and MUO groups. Cr, eGFR and BUN were studied. Total n = 277: MHO n = 105 vs MUO n = 172. Cr was higher and BUN was lower in MUO whereas eGFR did not differ between the groups. Using general linear model, we found that metabolic status predicted BUN (P = .009) but not Cr or eGFR. When age, sex and Tanner stage matched, BUN, Cr and eGFR were similar between the groups. Higher BUN in MHO could be due to higher dietary protein intake. Subjects were divided into BMI ≥40 vs <40 kg/m2 , BUN and eGFR were not different. A trend towards higher Cr in those with BMI ≥40 kg/m2 (P = .054) was found; the group being older and taller. After age and height matching, all outcomes were not different. Higher Cr was found in those with elevated blood pressures vs the MHO (P = .047). Those with diastolic blood pressure (DBP) ≥90th percentile had higher Cr than those with systolic blood pressure ≥90th percentile (P = .017). Children and adolescents with MUO, and those with BMI ≥40 kg/m2 did not appear to have early diminished kidney function. Higher Cr, although in normal range, occurred in those with abnormal DBP.

Challenging diagnosis of thyroid hormone resistance initially as Hashimoto's thyroiditis.

Background Resistance to thyroid hormone (RTH) commonly presents with goiter, attention deficit hyperactivity disorder (ADHD), short stature and tachycardia. However, due to its variable presentation with subtle clinical features, a third of the cases are mistreated, typically as hyperthyroidism. Case presentation A 15-year-old female with ADHD and oligomenorrhea was initially diagnosed as Hashimoto's thyroiditis but found to have a rare heterozygous mutation in c803 C>G (p Ala 268 Gly) in the THRß gene, confirming resistance to thyroid hormone. Conclusions Fluctuating thyroid function tests in addition to thyroid peroxidase antibody (TPO Ab) positivity complicated the diagnosis of RTH, initially diagnosed as Hashimoto's thyroiditis. A high index of suspicion is needed to prevent misdiagnosis and mistreatment.

National Survey Assessment of the United States' Pediatric Residents' Knowledge, Attitudes, and Practices Regarding Newborn Screening.

A pediatrician's approach to newborn screening (NBS) impacts patient care. Some physicians have reported not being well prepared to inform families about a positive NBS and recommend further follow-up. The knowledge and approach of categorical pediatric residents (RES) in the United States regarding NBS is not known. They were anonymously surveyed via listserv maintained by American Academy of Pediatrics. A total of 655 responses were analyzed. The mean composite knowledge score (CKS) was 17.7 (SD 1.8), out of maximum 21. Training level (p = 0.001) and completing NICU rotation (p < 0.001) predicted higher CKS. Most RES agreed that NBS is useful and pediatricians play an important role in the NBS process, however, only 62% were comfortable with counseling. Higher level RES were more likely to follow NBS results in clinic (p = 0.0027) and know the contact agency for results (p < 0.001). Most RES wanted more NBS training during residency and were not aware of clinical algorithms like ACTion sheets developed by American College of Medical Genetics. We concluded that although RES have sufficient knowledge about NBS, there is a need for earlier RES education on available tools for NBS to enhance their comfort level and improve practices such as educating parents about the NBS process.

Long-term follow-up of gonadal dysfunction in morbidly obese adolescent boys after bariatric surgery.

Background Elevated body mass index (BMI) is associated with hypogonadism in men but this is not well described in adolescents. The aim is to evaluate gonadal dysfunction and the effects of weight loss after gastric banding in obese adolescent boys. Methods Thirty-seven of 54 boys (age 16.2±1.2 years, mean BMI 48.2 kg/m2) enrolled at the Center for Adolescent Bariatric Surgery at Columbia University Medical Center had low total testosterone for Tanner 5 <350 ng/dL. Sixteen had long-term hormonal data for analysis at baseline (T0), 1 year (T1) and 2 years (T2) post-surgery. T-tests, chi-squared (χ2) tests, correlation and linear mixed models were performed. Results At T0, the hypogonadal group had higher systolic blood pressure (SBP) (75th vs. 57th percentile, p=0.02), fasting insulin (19 vs. 9 µIU/mL, p=0.0008) and homeostatic index of insulin resistance (HOMA-IR) (4.2 vs. 1.9, p=0.009) compared to control group. Total testosterone was negatively correlated with fasting insulin and HOMA-IR. In the long-term analysis, BMI, weight, waist circumference (WC), and % excess weight decreased at T1 and T2 compared to T0. Mean total testosterone at T0, T1 and T2 were 268, 304 and 368 ng/dL, respectively (p=0.07). There was a statistically significant negative correlation between BMI and testosterone after 2 years (r=-0.81, p=0.003). Conclusions Low testosterone levels but unaltered gonadotropins are common in this group and associated with insulin resistance. While a significant increase in testosterone was not found over time, the negative relationship between BMI and testosterone persisted, suggesting there may be an optimal threshold for testosterone production with respect to BMI. Long-term studies are needed.

Screening for autoimmune thyroiditis and celiac disease in minority children with type 1 diabetes.

BACKGROUND: Hashimoto's thyroiditis (HT) and celiac disease (CD) are commonly associated with type 1 diabetes (T1DM). There is no consensus on screening, however, the American Diabetes Association (ADA) and the International Society for Pediatric and Adolescent Diabetes (ISPAD) recommend testing for thyroid function (TFT), thyroid antibodies and anti-tissue transglutaminase antibodies (TTG) IgA soon after diagnosis. TFT should be repeated every 1-2 years while TTG IgA should be tested for within 2 and 5 years. We hypothesize that the rate of HT and CD in our T1DM children is lower, so screening may need to be revised to reflect their underlying risk. METHODS: An Institutional Review Board (IRB)-approved retrospective chart review was conducted on children with T1DM in the past 10 years. Age, sex, race, A1C, TFT, thyroid and celiac antibodies were obtained. t-Tests, the Wilcoxon-Mann-Whitney test and stepwise regression were performed. RESULTS: Of 222 children with T1DM, with a mean age of 15.8±5.53 years, followed for 6.1±4.0 years, 53% female, mean A1C 11.1±1.9% and 87% African American (AA). Three had Graves' disease (1.3%), three had HT (1.3%) and 97% were euthyroid. TFT were assessed on average every 1.3 years and thyroid antibodies every 2.5 years. Positive thyroid antibody was found in 11%, negative in 57% and unknown in 32%. The positive antibody group had higher mean A1C and TSH. No biopsy confirmed cases of CD (0%) were found when screened every 2.3 years. CONCLUSIONS: The number of individuals who screened positive for hypothyroid HT and CD was lower than expected in our population. Further studies are needed to assess the optimal screening frequency for HT and CD in minority children with T1DM.

Metformin Use in Children and Adolescents with Prediabetes.

With the increasing incidence of childhood obesity, clinicians need to understand its comorbidities and their management. The American Diabetes Association recommends pediatricians screen high-risk overweight and obese children. Identifying and treating prediabetic children and adolescents can help to reduce the burden of type 2 diabetes. Lifestyle interventions are pivotal. Metformin is the only oral medication approved for diabetes treatment in children. It has been studied in clinical trials in nondiabetic children and has been shown to have beneficial effects on body weight. Effects on diabetes prevention have not been studied and long-term data are limited in the pediatric population.

Comparison of A1C to Oral Glucose Tolerance Test for the Diagnosis of Prediabetes in Overweight and Obese Youth.

IN BRIEF This study reports performance of A1C against the oral glucose tolerance test (OGTT) in predicting prediabetes among overweight and obese African-American and Caribbean children. A retrospective chart review was completed for 230 children. Receiver operating characteristic curves were generated to find the predictive performances of different tests against the OGTT. A1C alone is a poor discriminator of prediabetes in our study population, with low sensitivity (70%) and specificity (48.8%). BMI z score, A1C, and homeostatic model assessment of insulin resistance are significant predictors of prediabetes and, when taken together, provide better discrimination for prediabetes.

Bariatric Surgery in Adolescents: Is Routine Nutrient Supplementation Sufficient to Avoid Anemia Following Bariatric Surgery?

BACKGROUND: Anemia following bariatric surgery is a known complication. To prevent nutrient deficiencies, adolescents require multivitamin/mineral supplementation following bariatric surgery. The purpose of this study was to investigate if routine multivitamin/mineral supplementation is sufficient to prevent anemia in adolescents undergoing bariatric surgery, particularly sleeve gastrectomy (SG), a procedure that may induce nutrient malabsorption. METHODS: We conducted a retrospective review of pediatric patients who underwent SG (34 patients) and laparoscopic adjustable gastric banding (LAGB) (141 patients) (January 2006 through December 2013). We examined anemia marker levels (iron, ferritin, folate, B12, hemoglobin, and hematocrit) at first visit and 3, 6, and 12 months postsurgery by repeated-measures analysis adjusting for weight loss. RESULTS: Following SG, folate levels decreased 3 and 6 months postsurgery but returned to baseline levels at 12 months. Furthermore, the SG group demonstrated lower folate levels compared with LAGB at 3 and 6 months. B12 levels decreased 6 months post-SG but returned to baseline at 12 months. Following LAGB, B12 levels decreased 12 months postsurgery compared with baseline. Ferritin levels decreased 3 months post-LAGB but returned to baseline levels at 6 months. There were no changes within groups or differences between groups in iron, hemoglobin, or hematocrit. CONCLUSIONS: While anemia did not occur in any patients while on recommended routine supplementation, folate levels were significantly reduced following SG and were lower in SG compared with LAGB patients. Additional folate supplementation seemed to improve folate levels, which highlights the importance of ongoing surveillance by primary care providers and the need for additional folate supplementation following SG.

A Unique Case of Bilateral Hürthle Cell Adenoma in an Adolescent.

BACKGROUND: Hürthle cell (HC) neoplasms are rare among pediatric thyroid cancers. HC adenomas (HCA) are typically benign and localized unilaterally without recurrence, and they are thus treated by hemithyroidectomy. HC carcinomas (HCC) can be bilateral and are more aggressive, necessitating total thyroidectomy. Diagnosis relies upon surgical histopathology demonstrating invasion for classification as HCC or lack of invasion in HCA, since fine needle aspiration fails to differentiate between the two. METHODS: We report a case of a 14-year-old adolescent female with bilateral HCA. She had an initial left hemithyroidectomy for a large nodule measuring 2 × 1.5 × 1.2 cm3 in the left lobe, while smaller subcentimeter nodules remained under surveillance in the right. One year later, a nodule in the right lobe doubled in size, necessitating a right hemithyroidectomy which also revealed HCA. CONCLUSION: To our knowledge, this is the first reported case of bilateral HCA in pediatrics. It highlights the importance of close surveillance of persistent small nodules, even in patients with previously documented benign lesions such as HCA, which are typically thought to be unilateral and localized. Both HCA and HCC remain unpredictable in behavior, and treatment of HCA should be individualized.

Exenatide Effects on Cardiometabolic Risk and Weight in Adolescents with Morbid Obesity and Type 2 Diabetes Mellitus: Two Case Reports.

OBJECTIVE: Glucagon-like peptide-1 (GLP-1) receptor agonists improve glycemic control and cardiometabolic risk factors in adults with type 2 diabetes mellitus, but pediatric data is sparse. RESEARCH DESIGN AND METHODS: This is the first report to describe the effects of GLP-1 receptor agonist Exenatide on metabolic risk and weight in adolescents with morbid obesity (BMI>35kg/m2) and type 2 diabetes in the first 6 months after treatment initiation. Two patients with morbid obesity who failed conventional therapy with insulin glargine and Metformin were treated with the addition of Exenatide. Metabolic parameters were obtained at 3 and 6 months post intervention. RESULTS: Improvements in cardiometabolic risk factors, such as fasting glucose and triglyceride levels, as well as HbA1c, were reached at 6 months compared to baseline. CONCLUSIONS: Our cases highlight the therapeutic potential of exenatide for adolescent patients with morbid obesity and type 2 diabetes.

Evaluation of puberty by verifying spontaneous and stimulated gonadotropin values in girls.

BACKGROUND: Changes in pharmacological agents and advancements in laboratory assays have changed the gonadotropin-releasing hormone analog stimulation test. OBJECTIVE: To determine the best predictive model for detecting puberty in girls. SUBJECTS: Thirty-five girls, aged 2 years 7 months to 9 years 3 months, with central precocious puberty (CPP) (n=20) or premature thelarche/premature adrenarche (n=15). METHODS: Diagnoses were based on clinical information, baseline hormones, bone age, and pelvic sonogram. Gonadotropins and E2 were analyzed using immunochemiluminometric assay. Logistic regression for CPP was performed. RESULTS: The best predictor of CPP is the E2-change model based on 3- to 24-h values, providing 80% sensitivity and 87% specificity. Three-hour luteinizing hormone (LH) provided 75% sensitivity and 87% specificity. Basal LH lowered sensitivity to 65% and specificity to 53%. CONCLUSIONS: The E2-change model provided the best predictive power; however, 3-h LH was more practical and convenient when evaluating puberty in girls.

A case of complete androgen insensitivity syndrome with a novel androgen receptor mutation.

We report a case of a 14-year-old girl with primary amenorrhea and phenotypic as well as hormonal features of complete androgen insensitivity syndrome (CAIS), who tested positive for a novel missense androgen receptor gene mutation resulting in serine-to-isoleucine change at position 703 in exon 4 in the ligand-binding domain. The interesting features of this case include a persistence of Müllerian derivatives, Sertoli cell adenoma, Tanner III pubic hair, and a normal bone mineral density. These features are not typically described in CAIS. This novel mutation associated with a unique clinical presentation serves to significantly enrich the literature on this rare and fascinating disorder of androgen insensitivity syndrome.