bluuebunny/crossref_metadata_2025 huggingface dataset:
Trends in HbA1c Change Among Youth Referred to a Pediatric Type 2 Diabetes Prevention Clinic
Authors: Paprocki Emily , Yan Yun , Lee Brian R , Barnes Mitchell , De Luca Francesco , Halpin Kelsee
Published: May 2021

Background: Pediatric type 2 diabetes (T2D) has increased in prevalence as childhood obesity rates climb. More youth are being referred to pediatric endocrinology due to the concern for developing T2D, yet prediction of which children will progress to overt T2D is challenging. We describe a single center experience with pediatric prediabetes referrals and trends in HbA1c change.

Methods: Retrospective review of new patients seen at a Type 2 Diabetes Prevention (T2DP) Clinic July 2015 - December 2019. All children referred to T2DP Clinic have an elevated BMI and findings of insulin resistance/prediabetes/early T2D. They are evaluated by pediatric endocrinology providers and dieticians at each visit.

The outcome of interest was categorical HbA1c change between patients’ initial and most recent T2DP Clinic visit. Only HbA1c measurements conducted at the study site were included to address inconsistencies in lab assays. HbA1c at the initial visit was categorized into 3 groups: 1) < 5.7%; 2) 5.7 to <6.5%; 3) 6.5% to <8.5%. Final HbA1c was categorized similarly with the option to progress to a 4th HbA1c group of ≥8.5%. Patients were categorized as progressors, regressors, or stable depending on change in group (e.g., group 1 --> group 2) between initial and most recent HbA1c. Comparisons between groups were made using ANOVA and Fisher’s exact tests.

Results: Among 297 patients seen for an initial visit, mean BMI z-score was 2.3 and body fat percentage was 44%. High blood pressure occurred in 47%, high ALT in 24%, low HDL in 14%. Prevalence of initial HbA1c < 5.7%, 5.7 to < 6.5%, and 6.5% to < 8.5% was 46%, 42%, and 12%, respectively. One-third (31%) were prescribed metformin at their initial visit.

Only 63 patients (21%) had 2 or more visits in the T2DP Clinic with study site HbA1c data available. Of those 63 patients, mean age at initial visit was 12.5 years, BMI z-score 2.0, and body fat 46%. Most patients were female (68%) with public insurance (70%). Race/ethnicity was 35% black, 29% white, 30% Hispanic. Mean time between initial and most recent HbA1c was 11.9 months. Assessment of categorical HbA1c change showed 14% of patients with progression (n=9), 65% stable (n=41), and 21% with regression (n=13). Female sex, ALT elevation, HbA1c, fasting glucose were found to be statistically different between the groups at baseline (p < 0.05). Age, race/ethnicity, BMI, body fat percentage, elevated blood pressure, lipid profile, 120-minute glucose on OGTT, and metformin use were not different between the groups.

Conclusions. Only 14% of children who presented for follow up in our T2DP clinic demonstrated progression in HbA1c. Risk factors for those who progress include female sex and ALT elevation. Further development of predictive models to identify this high-risk population who will progress is necessary. Retaining consistent follow up in pediatric prediabetes clinics presents a challenge.
Trends of Diabetes and Prediabetes Prevalence Among Korean Adolescents From 2007 to 2018
Authors: Kim Jihyun , Lim Jungsub
Published: May 2021

Background: To provide updated prevalence data and to estimate changes in the prevalence of diabetes among Korean adolescents by sex and age between 2007 and 2018. Methods: We used the data of children and adolescents (8,718 subjects aged 10 to 18 years) from the Korea National Health and Nutrition Examination Survey IV-VII (KNHANES 2007-2018). The recent prevalence of diabetes and pre-diabetes estimated by using the latest KNHANES VII. The linear trends were estimated by comparing 3-year KNHANES cycles according to sex and by using logistic regression. Results: The prevalence of diabetes and pre-diabetes was 0.298% (95% CI, 0.289-0.308) and 7.914% (95%CI, 0.43-0.49). The prevalence of diabetes was a significant increase from 0.189 to 0.430 during KNHANE IV and VII. A positive linear trend is significant for diabetes (p trends=0.006) in only male subjects. The prevalence of pre-diabetes was a significant increase from 5.86 to 12.08 in both sexes. During KNHANES IV and VII, the prevalence of obesity increased significantly. Conclusion: Between 2007 and 2018, the prevalence of diabetes among Korean adolescents increased. Further studies are required to determine the causes of these increases.
Economic Burden of Growth Hormone Deficiency in a US Pediatric Population
Authors: Kaplowitz Paul B , Manjelievskaia Janna , Lopez-Gonzalez Lorena , Marrow Cynthia D , Pitukcheewanont Pisit , Smith Alden
Published: May 2021

Pediatric GHD is a rare disorder of short stature that is currently treated with daily injections of GH. In addition to short stature, GHD is associated with other comorbidities such as impaired musculoskeletal development, cardiovascular disease, and decreased quality of life. The objective of this study was to analyze GH utilization, adherence, and healthcare costs among children with GHD who had either Medicaid or commercial health insurance. Children (age <18 years) with a diagnosis of GHD between January 1, 2007, and December 31, 2017 were identified in the IBM Marketscan Commercial and Medicaid Databases. Children with GHD were direct matched (1:3) to controls without GHD (or other short stature-related disorder) on age, gender, plan type, region, and race (Medicaid only). The index date was set as the date of the first GHD diagnosis during the selection window for GHD patients and using random assignment for controls. Patients were followed for the 12 months prior to the index date until the end of continuous database enrollment or December 31, 2018. Baseline comorbidities and medications were measured during the 12 months pre-index. Treatment patterns and all-cause and GHD-related healthcare costs were measured during the variable follow-up period. Multivariable modeling was used to compare costs between GHD patients and controls and between GH treated and untreated GHD patients while adjusting for baseline characteristics. There were 6,820 Medicaid and 14,070 commercial patients with GHD who met the study inclusion criteria. Mean (SD) age at index was 9.5 (4.5) years for Medicaid patients and 11.1 (3.7) years for commercial patients. A majority of patients were male (>65%) and followed for at least 3.7 years. Overall, 63.2% of Medicaid and 68.4% of commercial patients were treated with GH during follow-up. Among Medicaid patients, the treatment rate was highest among white males and lowest among black females. Adherence, as measured by proportion of days covered, was low, with 18.4% of Medicaid patients and 32.3% of commercial patients considered “adherent” (PDC ≥ 0.8). Nearly half (49.1%) of treated Medicaid patients and 24.3% of commercial patients discontinued GH therapy before age 13. After adjusting for baseline characteristics, all-cause non-GH costs were 5.7times higher (Δ$19,309) for Medicaid patients and 5.5 times higher (Δ$12,305) for commercial patients than matched non-GHD controls. Adjusted all-cause non-GH costs were 0.6 times lower (Δ$14,416) for treated Medicaid patients and 0.7 times lower (Δ$7,650) for treated commercial patients than for untreated patients. Pediatric GHD presents a significant healthcare burden, and many patients remain untreated or undertreated. Untreated GHD was associated with higher non-GH healthcare costs than treated GHD. Strategies to improve adherence may reduce the healthcare burden faced by these patients.
LUM-201 Elicits Greater GH Response than Standard GH Secretagogues in Pediatric Growth Hormone Deficiency
Authors: Bright George , Smith Roy , Thorner Michael O
Published: May 2021

Presentation Type: OralScience Type and Topic: Clinical Trial Introduction: LUM-201 (ibutamoren, formerly MK-0677) is an orally administered GH-secretagogue that stimulates the GH secretagogue receptor (GHSR1a) in the hypothalamus and pituitary. LUM-201 is in development for long-term use in a subset of PGHD patients with moderate growth deficiencies. A diagnosis of PGHD is confirmed by low GH responses to standard GH secretagogues (clonidine, arginine, L-dopa, glucagon, insulin) so it is somewhat counter-intuitive to suggest that children who cannot respond to one GH secretagogue might have favorable responses to LUM-201. Objective: To determine if LUM-201 stimulates GH responses differently than standard GH secretagogues. Methods: 68 naïve-to-treatment, prepubertal children with GHD received two standard GH stimulation tests and a test with a single 0.8 mg/kg dose of LUM-201. The 68 subjects included 20 girls and 48 boys. The median (interquartile range) age was 9.2 years (7.2,10.8), bone age 6.0 years (4.5, 7.9), height SDS -3.3 (-4.5, -2.5), pretreatment height velocity 4.0 cm/y (3.2, 4.6), and baseline IGF-1 51 ng/mL (24,111). Results: The median (interquartile range) of maximal GH response to single dose LUM-201 was 15.0 ng/mL (3.5, 49) and to various pairs of standard stimuli was 5.4 ng/mL (1.8-7.6) (p< 0.00001). The median (IQR) for the difference between GH responses to LUM-201 and standard stimuli was 9.6 ng/ml (1.9, 42). In a multivariate analysis (r2 =0.73) differential GH increased with higher values of baseline IGF-I (p < 0.00001) and standard GH stimulation test (p = 0.047) but was not influenced by age (p = 0.16), sex (p = 0.28), baseline HV (p = 0.24), age-bone age differences (p = 0.33) or height-SDS (p = 0.75). Conclusion: In GHD children, the GH response to single dose LUM-201 greatly exceeds that observed with standard GH testing agents. The difference is greatest among patients with higher baseline values of IGF-I and higher GH responses to standard stimuli. The synergistic actions of LUM-201 on the physiological mechanisms regulating GH release explain why GH responses are greater in response to LUM-201 compared to traditional tests used to diagnose PGHD. Key words: LUM-201, GH deficiency, GH secretagogues, pediatrics, stimulation tests, short stature, pituitary, hypothalamus
Persistence of Use in Children Receiving Growth Hormone Therapy
Authors: Spataru Amalia , van Dommelen Paula , Arnaud Lilian , Masne Quentin Le , Quarteroni Silvia , Koledova Ekaterina B
Published: May 2021

Background: Long-term persistence of use and starting at the earliest possible age are associated with attainment of near-normal adult or final height in children who are treated with growth hormone therapy. However, there are many factors associated with a lack of persistence. Our aim was to study persistence of use in children with growth disorders using the easypod™ connected autoinjector e-device, which automatically records adherence data and can transmit them via an online portal (easypod™ connect). We investigated persistence of use, defined indicators of a long persistence of use, and developed a model to predict and identify children at risk of discontinuing treatment in the following 6 months. Data and Methods: Anonymized data from children transmitting over 10 injections between January 2007 and April 2020 were analyzed. A child was considered to discontinue the use if they had no injection in the last 6 months (before April 2020) or had an injection pause of at least 6 consecutive months. Persistence was estimated by Kaplan-Meier analyses and Weibull accelerated failure time modeling. To predict the individual risk of discontinuing the use in the following 6 months, individual survival probabilities curves were estimated for each patient still using the system, and the survival probabilities were then recalculated such that they were conditional on the fact that a child had already used the device for a certain time. The Harrell’s c-index was used to assess the algorithm performance. Results: Data were available for 17,651 children of whom 11,056 discontinued the use and 6,595 were still persistent in April 2020. Median persistence of use for all patients using the device was 2.1 years. There was a highly significant difference in median persistence of use between the regions: 1.0, 1.5 and 2.8 years in the available countries in the Asia-Pacific, America and Europe regions, respectively. Other indicators that had a significant positive impact on persistence of use were: at least one dose change a year, having auxological measurements recorded in the system (and if ‘Yes’, height standard deviation < -2 at start of use had an additional effect), starting treatment at an early age, adherence ≥85%, customized injection speed setting and being male. For the individual prediction, random survival forests showed the best performance (Harrell’s c-index=0.72). Conclusions: Data from the connected autoinjector e-device showed that the persistence of use was approximately 2 years in children with growth disorders. We were able to define 8 indicators that had a positive impact on persistence of use of which several indicators were related to patient management. Our prediction model can be used to identify children needing support to reach longer persistence of use and subsequently optimal clinical outcomes.
Human Adrenal Cortical Zone Changes With Aging
Authors: Tezuka Yuta , Atsumi Nanako , Blinder Amy , Rege Juilee , Giordano Thomas J , Rainey William E , Turcu Adina
Published: May 2021

Background: Previous adrenal morphological studies have shown that the zona reticularis (ZR) and the zona glomerulosa (ZG) decrease in size with aging. Although several lines of evidence indicate that the hypothalamic-pituitary-adrenal axis becomes hyperactive in elderly, little is known about age-related transformations of the adrenal zona fasciculata (ZF). Objectives: To investigate the morphological and functional changes of the adrenal cortex across the adult life span, with emphasis on: 1) the understudied ZF, and 2) potential sexual dimorphisms. Methods: We used immunohistochemistry to evaluate the expression of several cortical proteins: aldosterone synthase (CYP11B2), visinin-like protein 1 (VSNL1), 3β-hydroxysteroid dehydrogenase type II (HSD3B2), 11β-hydroxylase (CYP11B1) and cytochrome b5 type A (CYB5A). The ZF area was estimated by subtracting the VSNL1-positive (a ZG marker) area from the HSD3B2-expressing area (ZG and ZF). All captured images were quantitated by ImageJ. In addition, we employed liquid chromatography-tandem mass spectrometry to quantify the morning serum concentrations of 6 steroids: cortisol, 11-deoxycortisol (11dF), 17α-hydroxyprogesterone (17OHP4), 11-deoxycorticosterone (DOC), corticosterone, and androstenedione (A4). The Mann-Whitney U test and Spearman’s rank correlation coefficients were used for statistical analysis, as appropriate. Results: We included 60 adrenal glands from 30 men and 30 women, with ages between 18–86 years. The total cortical area was positively correlated with age (r=0.34, p=0.008), and this association was significant only in men (p=0.02). Both the total (VSNL1-positive) and functional ZG (CYP11B2-positive) areas declined abruptly with aging in men (r=-0.57 and -0.76, p=0.001 and p<0.0001, respectively), but not women (p=0.06 and 0.27, respectively). The CYB5A-positive area, marking the ZR, correlated negatively with age (r=-0.76, p<0.0001) in both sexes. In contrast, the estimated ZF area showed a strong positive correlation with age both in men (r=0.59, p=0.0006) and women (r=0.49, p=0.007), while CYP11B1-positive area remained stable across ages (p=0.86). Finally, we measured morning levels of 6 steroids in 149 men and 149 women, with ages between 21–95 years, matched for age and body mass index. Serum cortisol, corticosterone, and DOC levels remained relatively stable across ages (p=0.38, 0.64 and 0.25, respectively), while 11dF levels increased slightly with age (r=0.16 and p=0.007), particularly so in men (p=0.005). Expectedly, 17OHP4 and A4 declined with aging (r=-0.37 and -0.37, p<0.0001 for both). Conclusions: In contrast with the ZG and ZR, the ZF and the total adrenal cortex area enlarge with aging. An abrupt decline of the ZG occurs with age in men, but not in women, possibly contributing to sexual dimorphism in cardiovascular risk.
Intracellular Cholesterol Metabolism in Aldosterone-Producing Adenoma.~A Possible Association With Cellular Morphometry and Genotype~
Authors: Harashima Shogo , Yamazaki Yuto , Ono Yoshikiyo , Omata Kei , Tezuka Yuta , Morimoto Ryo , Nakamura Yasuhiro , Satoh Fumitoshi , Suzuki Hiroyoshi , Sasano Hironobu
Published: May 2021

Introduction: Primary aldosteronism (PA) is the most common cause of secondary hypertension. More than 70% of APAs have been reported to have KCNJ5 somatic mutation in Asian countiries. Patients with KCNJ5 mutated APAs generally harbor high plasma aldosterone concentration (PAC), and are mainly composed of clear tumor cells containing abundant lipid droplets. However, an association among intracellular cholesterol metabolism, morphological features and genotypes in tumor cells has remained virtually unknown.[Materials and methods]Three cholesterol receptors (SR-B1, LDL-R, VLDL-R) were immunolocakized in 25 APA cases (KCNJ5 mt: n= 15, WT: n=10) who underwent adrenalectomy at Tohoku University Hospital. Image analysis software (HALO, India Labs) was used to quantitatively analyze the intracellular localization and immunoreactivity and expored their correlation with genotype and clinical factors.[Results]LDL-R immunoreactivity was significantly lower in KCNJ5 mt group than WT group (P = 0.0369). In KCNJ5 mt group, a significant correlation was detected between LDL-R immunoreactivity and CYP11B2 (Aldosterone synthase), (P = 0.0271, ρ = 0.5684) but not in WT group. In addition, LDL-R immunoreactivity was significantly inversely correlated with tumor size (P = 0.0142, ρ = -0.6176) and PAC (P = <0.001, ρ = -0.7179) in mt group as well as in whole APA cases.[Discussion]This is the first study to compare cholesterol receptor expression profiles with morphological tumor cell subtype, genotype, and clinical data in APAs. Results indicated that KCNJ5 mt APAabundantly stored cholesterol ester in their cytoplasm and cholesterol uptake was less activated, resulting In rather efficient aldosterone biosynthesis in tumor cells. In addition, a significant correlation was detected between LDL-R and CYP11B2 with the abundant localization of LDL-R in tumor cells. Therefore, LDL-R could be a predominant resource of plasma lipoprotein uptake in aldosterone-producing tumor cells, especially for KCNJ5mt APAs.
A Case of Definitive Therapy in Persistent Congenital Hyperthyroidism Secondary to an Activating Variant of the TSHR Gene
Authors: Reynolds Sarah M , Shimy Kim J , Merchant Nadia
Published: May 2021

Background: Sporadic congenital non-autoimmune hyperthyroidism (SCNAH) causes permanent hyperthyroidism secondary to activating mutations in the TSHR gene. SCNAH usually presents during infancy and can be difficult to treat with antithyroid drugs or subtotal thyroidectomy.1 When adequate therapy is delayed, irreversible sequela such as craniosynostosis, growth failure, and cognitive delays may develop. Definitive therapy for children with SCNAH is recommended with no consensus on timing or type of intervention. Our case highlights the importance of early total thyroidectomy to optimize clinical outcomes in patients with SCNAH.

Clinical case: A now 3-year-old male was born small for gestational age (SGA) at 34 weeks gestation with biochemical and clinical signs of hyperthyroidism in the neonatal period. On day of life 6, his TSH was 0.02 mcU/mL (reference range 0.34-5.6 mcU/mL) and free thyroxine (T4) was 5.42 ng/dL (reference range 0.58-1.64 ng/dL). Methimazole (MMI) 0.3 mg/kg/day was started at that time, and the dose was titrated over 6 weeks of life to 0.8 mg/kg/day due to continued elevation of free T4 levels. Negative thyroid autoantibodies and normal maternal thyroid studies prompted genetic testing at 3 months of age. This testing revealed a heterozygous variant in the TSHR gene [c.842G->A (p.G116R)] that was determined to be pathologic. Despite frequent MMI dose changes and confirmation of medication adherence, high-dose MMI was not effective in consistently normalizing his TSH and free T4 levels in the first two years of life. Concerns for poor growth and hyperactive behavior were also present. A “block and replace” strategy was not feasible since the patient remained hyperthyroid even at MMI doses up to 0.8 mg/kg/day. Despite normal insulin-like growth factor 1 and insulin-like growth factor binding protein 3 levels, poor linear growth persisted with a height Z-score of -3.61 by age 3 years. While he was SGA at birth, his recurrent hyperthyroidism impeded catch-up growth potential, so treatment with growth hormone (rhGH) was initiated. His height Z-score improved to -2.39 after 9 months on rhGH dosed at 0.18 mg/kg/week. Due to the difficulty in consistently managing him medically with MMI, he underwent total thyroidectomy at age three.

Conclusion: There is currently no consensus on the timing of definitive therapy for children with SCNAH. This case highlights the importance of considering total thyroidectomy at an early age to avoid long-term sequela of persistent hyperthyroidism.

1. Gozu HI, Lublinghoff J, Bircan R, Paschke R. Genetics and phenomics of inherited and sporadic non-autoimmune hyperthyroidism. Mol Cell Endocrinol. 2010;322:125–34.
A Case of Preterm Ovarian Hyperstimulation Syndrome Presenting With Vaginal Bleeding
Authors: Rana Pratibha , George Lovya
Published: May 2021

Background: Preterm ovarian hyperstimulation syndrome (POHS) is a rare syndrome described in preterm female infants. This is associated with high serum estradiol and gonadotropin levels, multiple follicular ovarian cysts, and edema of the hypogastric, labial and upper leg regions. This usually occurs at 30 to 39 weeks post-conceptional age (PCA). Vaginal bleeding may or may not be present. We present an unusual case of POHS that had a delayed presentation at 5 months of age (45 weeks PCA) with vaginal bleeding. Case presentation: An extremely premature female infant presented with vaginal bleeding at 5 months of age. Workup revealed pubertal gonadotropins indicating ovarian hyperstimulation. She had mild swelling in the hypogastric region. No breast buds were palpable and there was no clitoromegaly. At the time LH (22.2 mu/ml), FSH (8.3 mu/ml), Estradiol (502.2 pg/mL), and Testosterone (111 ng/dL) were all highly elevated. Multiple ovarian follicles were visualized on her pelvic ultrasound, with generous ovarian dimensions: right ovary (3.6 x 1.6 x 1.9 cm, volume 5.7 cc) and left ovary (2.5 x 2.4 x 1.5 cm, volume 4.7 cc). The largest follicle measured 8.8 mm. The uterus was 3.3 x 1.3 x 1.7 cm, with endometrial stripe thickness of 3 mm. There was no endometrial or adnexal mass. Cosyntropin test showed adequate peak cortisol (32.6 mcg/dL). Her newborn screen had been normal. Serial monitoring of her lab work showed a decrease in her gonadotropin and estradiol levels. She had a recurrence of vaginal bleeding about 3 weeks after initial presentation. By 50 weeks PCA the bleeding had resolved and the LH (1.2 mu/ml), FSH (1.5 mu/ml), estradiol (36 pg/ml) had reduced considerably. Complete normalization of LH (1.2 mu/ml), FSH (1.5 mu/ml), E (36 pg/ml), and testosterone (<7 ng/dl) was demonstrated by 55 weeks PCA. Conclusion: POHS has been attributed to the immaturity of the hypothalamic-pituitary-gonadal axis in preterm infants. Vaginal bleeding has been described in one case [1] several weeks after breast enlargement and swelling of clitoral hood, labia majora, hypogastrium and upper legs. In our case the baby presented with vaginal bleeding at 45 weeks that recurred about 3 weeks later and resolved by 50 weeks, with only minimal swelling. This case underlines the need to be aware of this etiology and its varied presentation. [1] Preterm ovarian hyperstimulation syndrome presented with vaginal bleeding: a case report. Altuntas et al. J Pediatr Endocr Met; 273(3-4):355-358.
A Case of Psuedohypoparathyroidism Unmasked by COVID-19 and Rhabdomyolysis
Authors: Chan Jacqueline , Mansuri Asif
Published: May 2021

Background: Psuedohypoparathyroidism type 1 b (PHP 1b) is a rare condition characterized by hormone resistance with PTH. It is caused by imprinting defect of the GNAS gene and is acquired as autosomal dominant. Compared with Pseudohypoparathyroidism type 1a (PHP1a), PHP1b does not have the characteristic physical features know as Albright hereditary osteodystrophy or AHO. Results: 12-year-old female with unremarkable past medical history presented with seizures. She has been complaining of leg pain for a week but on the day of presentation noted to have stiffening and shortness of breath. There was no history of cough, fever, leg trauma, headache, dysuria, hematuria or dark urine. She had no significant family history. Work up revealed severe hypocalcemia of 4.6 mg/ dL and elevated phosphorus (7.1mg/dl). There was no hypoglycemia and other electrolytes including renal function were normal. Patient also had normal inflammatory markers, normal fibrinogen, and normal ferritin. Urine was positive for trace protein and was positive for myoglobin. Alkaline phosphatase was normal. Urine toxicology screen was negative. Hand X-rays did not showed the shortening of metacarpal bones and kidney ultrasound was normal. After IV calcium bolus, calcium barely increased at 5.0. Interestingly CK was noted to be elevated at 3,794 U/L. Patient physical exam was normal and there was no signs of Albright hereditary osteodystrophy (AHO). Patient was positive for COVID19. Patient required intensive fluid therapy to correct CK which increased up to 11,223 U/L on 3rd day of admission. It eventually came down back to normal on the 6th day. Creatinine levels remained normal. Patient continued to receive high dose calcium and calcitriol supplement and discharged with calcium of 8.5 mg/dL and phosphorus of 7.8 mg/dL. Additional work up showed PTH of 885 pg/mL consistent with pseudohypoparathyroidism. Vitamin D levels and thyroid function were normal. Genetic testing for pseudohypoparathyroidism is awaited. Conclusion: Psuedohypoparathyroidism type 1 b (PHP 1b) is a rare endocrine disorder presenting with hypocalcemia, hyperphosphatemia and increased PTH values due to a variable resistance to target organs. As in our case it was unmasked by COVID 19 infection and rhabdomyolysis. Best of our knowledge there is no such unusual case reported in children. Severe hypocalcemia likely due to combination of factors including tissue calcium deposition, hyperphosphatemia, and skeletal resistance to PTH. As published in some recent reports, this case also illustrates that rhabdomyolysis could be potential complication of SARS- CoV2 infection in early stage with normal renal function, which warrants further research.
Continuous Glucose Monitoring Facilitates Diazoxide Use in the Management of Glut1 Deficiency Syndrome
Authors: Logel Santhi N , Connor Ellen L , Hsu David A , Engelstad Kristin M , De Vivo Darryl
Published: May 2021

Background: Glut1 deficiency syndrome (Glut1DS) is caused by mutations in SLC2A1 on chromosome 1p34.2, which impairs transmembrane glucose transport across the blood brain barrier resulting in hypoglycorrhachia and decreased glucose availability for brain metabolism. This causes a drug-resistant, metabolic epilepsy due to energy deficiency. Standard treatment for Glut1DS is the ketogenic diet (KD) but treatment options are limited if patients fail the KD. Diazoxide, which inhibits insulin release, was used sparingly in the past for a few Glut1DS patients to increase blood glucose levels and thus intracerebral glucose levels. Unfortunately, their treatment was complicated by unacceptable persistent hyperglycemia with blood glucoses in the 300s to 500s. We investigated the use of a continuous glucose monitor (CGM) to enable titration of diazoxide therapy in a patient with KD-resistant Glut1DS.

Clinical Case: A 14-year-old girl with Glut1DS (c.398_399delGCinsTT:p.Lys133Phe) failed the KD due to severe nausea, vomiting, abdominal pain, and hypertriglyceridemia. Laboratory tests revealed CSF glucose of 36 mg/dL when blood glucose was 93 mg/dL. Over the course of 3 hospitalizations targeting blood glucose levels in the range of 120-180 mg/dL with diazoxide, EEG seizure activity decreased from 3 to 0 absence seizures per hour. CGM placement during the third hospitalization showed an average interstitial glucose of 157 mg/dL with glucose variability of 20.8% on diazoxide dose of 7.3 mg/kg/day. After discharge, CGM has been used to adjust diazoxide doses 2-4 times a week to achieve target interstitial glucoses of 140-180 mg/dL. Repeat laboratory tests revealed CSF glucose of 55 mg/dL when interstitial glucose was 158 mg/dL. Current diazoxide dose is 7.9 mg/kg/day and most recent hemoglobin A1c was 5.4%.

Conclusions: This is the first report demonstrating CGM as a tool facilitating the safe initiation and real-time titration of diazoxide in Glut1DS patients who have failed the KD. Diazoxide addresses neuroglycopenia more physiologically by raising blood glucose levels and subsequently intracerebral glucose levels. CGM allows for more accurate titration of blood glucose with diazoxide while avoiding complications of hyperglycemia and thus introduces the possibility of diazoxide becoming a standard of care for Glut1DS. More broadly, CGM provides a valuable tool for the management of other disorders of glucose transport and carbohydrate metabolism.
Continuous Glucose Monitoring in the Management of Hypoglycemia in TANGO2
Authors: Esper Brecken S , Carson Mallory , Galvin-Parton Patricia , Lane Andrew H , Tafuri Kimberly S
Published: May 2021

Introduction: The TANGO2 gene encodes a transport and Golgi organization protein of unclear function; mutations should be considered in patients presenting with acute metabolic crisis, hypoglycemic episodes, cardiac arrhythmias, and other endocrinopathies. We report the novel use of a continuous glucose monitor (CGM) to help predict and prevent significant hypoglycemic episodes in a patient with TANGO2 mutation.

Clinical Case: A 14-month old previously healthy, developmentally normal female who presented with unresponsive hypoglycemia (glucose 26 mg/dL) was demonstrated by Next Generation Sequencing to have a pathogenic 31.8 kb deletion of exon 3 to 9 in the TANGO-2 gene and a suspected pathogenic hemizygous c.569_592dup, p.Ile190_Leu197dup in TANGO-2. Her hospital course was notable for MRI showing hypoxic ischemic encephalopathy and both physical and electrical cardiac dysfunction. Continuous intravenous dextrose corrected the hypoglycemia, and transient hyperglycemia followed after several days of a glucose infusion rate between 3.2 to 5.8 mg/kg/min. After transitioning to ad lib oral feeds without restrictions, she was discharged.

A second admission for acute unresponsive hypoglycemia and metabolic acidosis (glucose 30 mg/dL) occurred at 17 months of age with no clear inciting cause. Continuous IV dextrose at 9.9 mg/kg/min corrected the hypoglycemia and again resulted in transient hyperglycemia up to 271 mg/dl. Levothyroxine was also started for a TSH of 27 mIU/mL and a T4 of 4.6 ug/dL. Immediately after discharge, a DexCom G6 CGM was placed. Data over 2 weeks shows an average glucose of 104 ng/dL with 99% of the BS in target range. Parents report that CGM predictive low alerts have allowed intervention to abort fasting-related metabolic crises.

Conclusion: In TANGO-2 deficiency, the liver may not adequately store and/or release glycogen in response to glucagon due to abnormal endoplasmic reticulum, Golgi apparatus, and mitochondrial functioning in states of stress or illness. Recent reports are conflicting with some showing reduced mitochondrial respiration in TANGO-2 patients in steady state with others finding normal values, opening the possibility that a combination of factors in the setting of stress may precipitate a metabolic crisis. Our patient quickly returns to near-normal physiological functioning; consequently, we suggest that use of a CGM can help prevent fasting related metabolic crisis in TANGO2 patients and can help guide feeding schedule and food choices to limit hyper- and hypoglycemia. In addition, CGM data can help further investigate if any beta cell dysregulation exists in non-acute states.

References: Bérat CM, ... & de Lonlay P. (2020). Clinical and biological characterization of 20 patients with TANGO2 deficiency indicates novel triggers of metabolic crises.... J Inherit Metab Dis. 2020 Sep 14. doi: 10.1002/jimd.12314.
Isolated Growth Hormone Deficiency as a Cause of Hypoglycemia Past Infancy
Authors: Thakkar Amruta , Aikaterini Nella
Published: May 2021

Introduction: Hypoglycemia is a common manifestation of Growth Hormone (GH) deficiency in infancy, but is rarely seen beyond 1 year of age. Here, we describe the case of a 5 year 6- month- old child with recurrent episodes of hypoglycemia due to GH deficiency in the setting of malnutrition. Experimental Methods / Case Presentation: Case report and literature review Results: A 5y6m girl with history of atypical teratoid rhabdoid tumor, status-post surgical resection and adjuvant therapy with CNS irradiation (50.4 gray), presented with recurrent hypoglycemia despite continuous G-tube feedings. Child had undergone surgery and irradiation approximately 3 years prior to presentation. She was initially followed at the cancer survivor clinic but had been lost to follow up for 2 years. At presentation, whole blood glucose was 51mg/dL. Height was 93.5cm (-4 SDS) and BMI 10.6 kg/m2 (- 7.75 SDS); she appeared malnourished on exam with minimal subcutaneous fat. She was admitted to the hospital where blood glucoses ranged from 59-68 mg/dL, despite continuous enteral feeds. On evaluation, blood ketones were mildly elevated at 0.67 mmol/L (ref range < 0.3mmol/L), growth factors were low: IGF1 15 ng/mL (ref range 37 - 272 ng/mL); IGF-BP3 1.1 mg/L (ref range 1.1 - 5.2 mg/L), and other pituitary hormones were within normal range [stimulation test cortisol peak 31.9 mcg/dL, TSH 2.4 mIU/mL(Ref range: 0.700 - 4.100 uIU/ML), Free T4 1.2 ng/dL (Ref range 1.0-2.4 ng/dL)]. Hypoglycemia resolved within 48 hours of initiating empiric treatment with GH (0.2mg/kg/week) and patient’s feeds were successfully compressed to 16 hours. Child was discharged home after passing an overnight 8-hour safety fast. Conclusion: Growth hormone deficiency can present as recurrent hypoglycemia outside the infantile period in the setting of malnutrition and needs to be considered in the differential diagnosis and evaluation of childhood hypoglycemia. ​
Maffucci Syndrome, Calcium Homeostasis, and Endocrine Challenges in Management
Authors: Ginnard Olivia Z B , Burrage Lindsay C , Karaviti Lefkothea P
Published: May 2021

Maffucci syndrome is a rare disorder characterized by enchondromatosis and hemangiomata. It can occur due to sporadic, de novo, mosaic pathogenic variants in the gene encoding isocitrate dehydrogenase 1 (IDH1) or isocitrate dehydrogenase 2 (IDH2). IDH1 variants are associated with endocrine manifestations, such as pituitary adenomas. However, literature is limited in describing other clinical features and available treatments in severe phenotypes. We report a pediatric patient with uniquely complex and severe Maffucci syndrome. Case: A 5-year-old boy was evaluated by pediatric endocrinology for chronic hypercalcemia as part of a multidisciplinary evaluation of his severe Maffucci syndrome. Past medical history included prematurity, restrictive lung disease, developmental delay, seizures, 2-OH glutaric aciduria, angiomas, and bicytopenia. Physical exam revealed angiomas, scoliosis, and severe bony deformities throughout the entire skeleton. During admission, laboratory assays revealed normal parathyroid hormone, phosphorus, 1,25-OH2D, and C-telopeptide; elevated serum calcium and PTH-related peptide; and low 25-OHD, alkaline phosphatase, and osteocalcin. Low-dose ACTH stimulation test yielded a peak cortisol level of 16.8. A 24-hour urine study confirmed hypercalciuria. Renal ultrasound demonstrated nephrocalcinosis. Skeletal survey revealed diffuse and chondromatous changes of nearly every bone. Whole-exome sequencing detected a presumed, mosaic de novo IDH1 variant. DEXA scan revealed total body BMD z-score of -3.8. Discussion: Hypercalcemia in Maffucci syndrome is a rare phenomenon. The most likely etiology was due to the severe and chronic bony breakdown from the underlying progressive enchondromatosis. Subsequently, the body attempted to adapt to these chronic processes with abnormal mineral homeostasis, as seen in his laboratory assays. Chronic primary hyperparathyroidism was not likely, as his PTH, phosphorus, and 1,25 OH2D levels were not congruent with that diagnosis. Familial hypocalciuric hypercalcemia was not likely, as his urine calcium clearance ratio was >0.01. Finally, his slightly elevated PTHrP level was not due to PTHrP-mediated hypercalcemia of malignancy, as his bone marrow biopsy was negative. The options for short-term hypercalcemia management had their own inherent risks and were not suitable for long-term management. Although there is a lack of pediatric data to guide therapy in Maffucci syndrome, decision was made to proceed with bisphosphonate infusion given the benefits in the setting of his nephrocalcinosis, chronic hypercalcemia, and results of his DEXA scan. Given the rarity of Maffucci syndrome, few characteristics are well-described in the pediatric population. A multidisciplinary approach is necessary to review the severity of the disease and to determine the best treatment approach based on this information.
Metreleptin and Metformin Use in an Infant With Congenital Generalized Lipodystrophy Secondary to AGPAT2 Mutation
Authors: Schweisberger Cintya , Jacobson Jill Diane , Paprocki Emily
Published: May 2021

Background: Congenital generalized lipodystrophy (CGL) is a rare inherited disease characterized by widespread loss of subcutaneous fat and severe metabolic abnormalities. Metreleptin, a synthetic analog of leptin, is a treatment modality that has been shown to decrease fasting triglycerides, fasting glucose, and HbA1c. Metformin use in infants has only been described in a few case reports of CGL and Donohue syndrome (insulin receptor mutation), and there is no established dosing for this age group. We report metreleptin, insulin, and metformin use in an infant with type 1 CGL who presented with marked hypertriglyceridemia, hypoleptinemia, hyperglycemia, and transaminitis.

Clinical Case: A 2-month-old African American female born SGA at term presented to her primary care physician for a well child check where she was noted to have poor weight gain, hyperphagia, and abdominal distension. She was subsequently admitted for failure to thrive with weight z-score of -2.17 and length z-score of -0.15. Initial labs were notable for triglycerides of 5,167 mg/dL, HDL 10 mg/dL, blood glucose 324 mg/dL, ALT 212 units/L, AST 215 units/L, and bicarbonate of 17 mmol/L. A random insulin level was elevated at 257 mcIU/mL. Adiponectin was undetectable and leptin was low at 0.3 ng/mL. Hemoglobin A1c was in diabetes mellitus range at 8.9%. She was started on detemir 1.0 units/kg/day on day 1 (titrated to a maximum dose of 4.4 units/kg/day) and metformin 50 mg/kg/day on day 3 of hospitalization. By day 4, triglycerides decreased to 758 mg/dL, AST to 119 units/L and ALT to 124 units/L. Pre-prandial glucoses improved ranging from 113 to 138 mg/dL. As her insurance denied coverage for detemir, she was discharged home on glargine 0.7 units/kg/day and metformin suspension. One month later, she was started on subcutaneous metreleptin, and glargine was discontinued. At 5 months of age, she had triglycerides 229 mg/dl, normal liver enzymes, and normal blood glucoses while on 0.056 mg/kg/day of subcutaneous metreleptin and metformin. Medications were well tolerated without side effects. She had improved growth and met all developmental milestones. Genetic evaluation revealed that she was homozygous for a pathogenic variant, c.589-2A>G; p.Gln196fs*228 (rs116807569), in the AGPAT2 gene.

Conclusion: Leptin is important in regulation of lipid and glucose metabolism, and patients with CGL are deficient due to lack of adipose tissue. Metabolic abnormalities, including stabilization of glucoses and improved hypertriglyceridemia, in our patient markedly improved with initiation of metreleptin, metformin, and insulin. We present successful dosing of these treatment modalities without adverse reactions in an infant with CGL.
Paternalism in DSD Management: A Real and Present Threat
Authors: Moryan-Blanchard Kristen , Karaviti Lefkothea P , Axelrad Marni , Austin Paul , Mann David
Published: May 2021

In 1965, a botched circumcision left Bruce Reimer, a healthy, 8-month old XY male, with a disfigured penis. At the recommendation of Dr. John Money and physicians at Johns Hopkins, the infant was reassigned to female sex and underwent an orchiectomy and vaginoplasty. The family renamed the child “Brenda.” Unaware of her history, Brenda struggled with significant gender identity, psychological, and behavioral issues throughout her childhood and adolescence. When made aware of this history, she transitioned to male gender and assumed the name “David.” After years of psychological distress, David Reimer committed suicide in 2004. Despite the myriad lessons gleaned from this tragic story, medical and surgical management of children with atypical genitalia still remains often misguided, as providers continue to assume paternalistic roles in determining sex assignment and surgical interventions. A fifteen year old XY male with Robinow Syndrome presented for evaluation of hypogonadism and urinary incontinence. At birth, the patient was discovered to have a micropenis and perineal hypospadias and was diagnosed with hypogonadotropic hypogonadism. At the recommendation of the medical team, the infant underwent bilateral orchiectomy at eight months of age followed by urethroplasty and vaginoplasty at six years of age. The child was then given a female sex assignment. At twelve years of age, the child felt discordant from the sex of rearing and wished to be identified as male—his natal, genetic sex. He transitioned to male gender and began testosterone injections. He had history of recurrent UTIs and severe incontinence requiring diaper use. He strongly desired neophallus and urethral reconstruction for improved quality of life. The patient endorsed prior depression and desires to self-harm. He had significant concerns regarding his gender presentation and transition. He shared his difficulties in continuing in the same school system with peers who knew him as a female prior to transition and was concerned about peers knowing his medical history. In the years since the famous David Reimer case, the medical system has made tremendous strides in recognizing the need for patient autonomy and shared decision-making in patients with Differences of Sex Development and genital atypia. However, the paternalistic history of this field continues to leave its indelible mark more than 20 years since David Reimer’s case made headlines, as physicians continue to recommend definitive sex assignments and surgical interventions. As with the David Reimer case, the bodily integrity of this XY infant was altered in a permanent fashion with inadequate education of his family and little to no credence given to the autonomy of the child himself. We, as physicians, cannot continue to paternalistically apply John Money’s concept of gender neutrality and rigidly mandate sex assignments and early surgical interventions.
Steroid Cell NOS in a Child: A Rare Case Report
Authors: Paladugu Sridevi
Published: May 2021

Introduction: Steroid cell tumors are rare sex chord tumours of the ovary with malignant potential. Here we report a case of steroid cell NOS in a 12-year-old girl & similarity of the clinical presentation with non-classic congenital adrenal hyperplasia.

Clinical Case: 12-yr girl came with complaints of hirsutism since many years and a recent change in voice. There was no past history suggestive of adrenal crisis. On examination she had muscular body habitus, moderate hirsutism (FG score 19), acne. SMR B1, P4, A3. Karyotype 46 XX. BA 13yrs. DHEAS- 144, serum cortisol 8am-14ug/dl. Testosterone-8.35ng/ml (normal 0.1-0.9ng/ml). serum 17 (OH) Progesterone basal-16.37 ng/ml(N-0.2-1.3ng/ml). Post synacthen 17OHP >35ng/ml, LH- <0.1, FSH- 0.2(prepubertal range). U/S-adrenals normal, right ovary was enlarged in size, 4x3cm cystic lesion. A CECT ABDOMEN showed Rt ovary -homogenously enhancing fairly well-defined solid lesion. Differential diagnosis was: NC/SVCAH with ovarian rest tumours vs ovarian virilising tumour. Since there was no non-invasive way of confirming between both the diagnosis, we gave a trial with hydrocortisone to see if her 17OHP reduces. After 1 month of therapy with hydrocortisone,17 OHP was still elevated -17.08ng/ml. Since there was no response, she underwent ovarian biopsy/excision. Right ovarian cystectomy was done. HPE showed -consider1. Steroid cell tumour NOS 2. Adrenal rest tumour. Note that these 2 tumours have identical morphology & IHC features. Followup:2 mon post-surgery: B5 P4 A3, mild facial hair,17 OHP - 1.53 ng/ml, Testosterone 2.5 ng/dl.12 months post-surgery child attained menarche had regular menstrual cycles, Serum 17OHP- 0.41 ng/ml, testosterone-11ng/dl.

Conclusion: The usual differential diagnosis in 46 XX female children presenting with signs of androgen excess is CAH, it is not uncommon to find SVCAH presenting in childhood with symptoms & signs of virilisation. Clinically both SV CAH and Steroid cell tumours can present with hyperandrogenic features in the childhood. Amongst steroid cell tumours, 3 subtypes are seen, they include 1. stromal luteoma 2. Leydig cell tumour 3. steroid cell tumour NOS. The steroid cell tumours of the ovary secrete androstenedione, alpha hydroxy progesterone & testosterone .17OHP is raised in both the conditions. The HPE of both adrenal rest tumours & steroid cell NOS is similar & a clear-cut differentiation cannot be made. They are similar in clinical presentation, biochemistry & HPE. It is important to recognise that steroid cell tumour NOS is a differential to SVCAH in childhood. Since these tumours can occur at any age, clues to differentiate both conditions are-raised 17OHP but normal DHEAS & on imaging- normal adrenals with enlarged ovaries with or without solid cystic lesions in steroid cell NOS of the ovary.