Pediatric Cushing syndrome: An early sign of an underling cancer predisposition syndrome.

Beckwith-Wiedemann syndrome (BWS) is a genetic overgrowth and cancer predisposition syndrome that can be associated with a spectrum of clinical features including isolated lateralized overgrowth, macrosomia, macroglossia, organomegaly, omphalocele/umbilical hernia, and distinct facial features. Because of a range of clinical presentations and molecular defects involving Chromosome 11p15, many cases will fall within what is now being defined as the Beckwith-Wiedemann spectrum (BWSp). Cushing syndrome (CS) in infants is a rare neuroendocrinological disease associated with hypercortisolism that has rarely been reported in patients with BWS. Here, we describe the first case of a 5-month-old male with CS secondary to paternal uniparental disomy of Chromosome 11p without additional clinical signs or symptoms of BWS. This case continues to expand the phenotypic spectrum of BWSp.

Whole genome sequencing identifies a cryptic SOX9 regulatory element duplication underlying a case of 46,XX ovotesticular difference of sexual development.

Ovotesticular differences of sexual development (OT-DSD) are rare genetic variances defined by the coexistence of both testicular and ovarian tissues. Various molecular etiologies including SRY translocation or SOX9 pathogenic variants with different modes of inheritance have been associated with 46,XX OT-DSD. Here we describe a child diagnosed with SRY-negative 46,XX OT-DSD after completing a series of complex clinical genetic analyses, including chromosomal microarray, DSD gene panel (sequencing and deletion/duplication analysis), whole exome sequencing, and whole genome sequencing. Of these, only whole genome sequencing reported a pathogenic duplication in a non-coding region that contains the RevSex regulatory element, which modifies SOX9 expression and is associated with 46,XX OT-DSD and complete sex reversal. This is the first clinical RevSex duplication detected by clinical whole genome sequencing. We highlight the utility of whole genome sequencing in shortening the diagnostic odyssey and the importance of optimal counseling through a team-based multi-specialty approach for patients with DSDs.

A Reversible Etiology of Progressive Motor Decline in a Previously Healthy Child.

We describe the clinical presentation and evaluation of a 10-year-old boy who presented to our medical center with years of progressive proximal muscle weakness, muscle atrophy, and weight loss. In addition to a myopathic phenotype, he was found to have tachycardia, tremor, and learning difficulties. Electromyography revealed chronic myopathic changes and laboratory screening was notable for undetectable thyroid stimulating hormone. Follow-up testing revealed elevated thyroid peroxidase antibodies and thyroid stimulating immunoglobulins. Ultrasound examination revealed an enlarged heterogeneous thyroid gland. Four weeks after treatment with atenolol and methimazole, his strength and cognition began to improve. This case highlights the importance of evaluating for potentially reversible toxic-metabolic etiologies in children presenting with any progressive neurologic symptoms.

Congenital hyperinsulinism in a newborn presenting with poor feeding.

Hyperinsulinemic hypoglycemia is a condition linked to several genetic, metabolic, and growth disorders in which there is dysregulated insulin secretion. In infants, an inappropriately persistent hypoglycemic and hypoketotic state can cause severe brain injury leading to epilepsy, cerebral palsy, and neurodevelopmental disabilities due to the lack of glucose and ketone substrate to serve as fuel for the developing brain. The most common cause of persistent hypoglycemia in neonates and children has been found to be congenital hyperinsulinism. Here, we report a child with a unique presentation, found to have a novel genetic variant as the underlying cause of hyperinsulinism. This case study highlights the importance of maintaining a broad differential and considering a diagnosis of congenital hyperinsulinism in a baby with poor feeding in the newborn period. Recognizing and treating congenital hyperinsulinism is essential to prevent potential neurological sequelae from recurrent, severe hypoglycemia.

Menarche delay and menstrual irregularities persist in adolescents with type 1 diabetes.

BACKGROUND: Menarche delay has been reported in adolescent females with type 1 diabetes (T1DM), perhaps due to poor glycemic control. We sought to compare age at menarche between adolescent females with T1DM and national data, and to identify factors associated with delayed menarche and menstrual irregularity in T1DM. METHODS: This was a cross-sectional study and females ages 12- 24 years (n = 228) with at least one menstrual period were recruited during their outpatient diabetes clinic appointment. The National Health and Nutrition Examination Survey (NHANES) 2001-2006 data (n = 3690) for females 12-24 years were used as a control group. RESULTS: Age at menarche was later in adolescent females with T1DM diagnosed prior to menarche (12.81 +/- 0.09 years) (mean+/- SE) (n = 185) than for adolescent females diagnosed after menarche (12.17 0.19 years, p = 0.0015) (n = 43). Average age of menarche in NHANES was 12.27 +/- 0.038 years, which was significantly earlier than adolescent females with T1DM prior to menarche (p < 0.0001) and similar to adolescent females diagnosed after menarche (p = 0.77). Older age at menarche was negatively correlated with BMI z-score (r = -0.23 p = 0.0029) but not hemoglobin A1c (A1c) at menarche (r = 0.01, p = 0.91). Among 181 adolescent females who were at least 2 years post menarche, 63 (35%) reported usually or always irregular cycles. CONCLUSION: Adolescent females with T1DM had a later onset of menarche than both adolescent females who developed T1DM after menarche and NHANES data. Menarche age was negatively associated with BMI z-score, but not A1c. Despite improved treatment in recent decades, menarche delay and high prevalence of menstrual irregularity is still observed among adolescent females with T1DM.

Acquired growth hormone deficiency in a girl with chronic myelogenous leukemia treated with tyrosine kinase inhibitor therapy.

Chronic myelogenous leukemia (CML) is caused by the BCR-ABL1 fusion gene that encodes for a constitutively-active tyrosine kinase. Adults and children with CML are typically treated with imatinib mesylate, a BCR-ABL1 tyrosine kinase inhibitor (TKI), or a second-generation TKI. Several case reports have documented growth delay of unknown mechanism in children with CML treated with imatinib. We report a seven-year-old identical twin with CML who developed significant growth delay, as compared to her twin, during five years of TKI therapy. Detailed endocrine evaluation showed acquired growth hormone deficiency, a pathway potentially inhibited by TKIs.

A Case Series of Patients With Central Hypothyroidism From Oxcarbazepine Therapy.

Many medications can impact thyroid function. Antiseizure medications have been shown to disrupt thyroid function in adults, but information is limited about how antiseizure medications may affect thyroid function in children. Oxcarbazepine is an analog of carbamazepine designed to minimize effects from the hepatic P450 metabolic enzymes. We have found that in the pediatric population, serum free thyroxine is reduced and thyroid-stimulating hormone concentrations are unchanged in patients taking oxcarbazepine with the mechanism thus being central hypothyroidism.

Case report: severe neonatal hyperkalemia due to pseudohypoaldosteronism type 1.

Hyponatremia and hyperkalemia in infancy can represent a variety of renal and genetic disorders with significant long-term health implications. We report a newborn with severe hyperkalemia and hyponatremia from autosomal recessive pseudohypoaldosteronism type 1 requiring aggressive therapy. The evaluation and treatment of children with disorders of mineralocorticoid action are discussed.

Surgical management of neck pain and headache associated with pediatric hashimoto's thyroiditis.

OBJECTIVES/HYPOTHESIS: Case reports of a painful variant of Hashimoto's thyroiditis exist in the literature; however, these cases have only been documented in adult patients and there are no standard treatment guidelines. The aim of this study was to describe an alternative management for Hashimoto's thyroiditis associated with medically intractable head and neck pain in the pediatric population. STUDY DESIGN: Case series with chart review. METHODS: The study was conducted in the Section of Pediatric Otolaryngology at the Cleveland Clinic. We retrospectively analyzed pediatric patients (ages 0-18 years) with painful thyroiditis and/or headache who underwent total thyroidectomy from 2005 to 2014 with a clinical diagnosis of Hashimoto's thyroiditis. A thorough chart review was performed, including medical and family history, presenting symptoms, laboratory values, medical and surgical treatment strategies, operative reports, and surgical pathology. RESULTS: There were 0.02% of patients (5 of 305) who met the criteria of intractable head and or neck pain. All five underwent total thyroidectomy with confirmation of Hashimoto's thyroiditis on surgical pathology. Surgical treatment resulted in complete cervical pain relief and improved headaches with a minimum follow-up of 36 months. CONCLUSIONS: Hashimoto's thyroiditis is a relatively common form of autoimmune thyroiditis in pediatric patients that uncommonly results in intractable neck pain or headache. In this case series, thyroidectomy was an effective alternative treatment in the pediatric population for medical failures in chronic painful Hashimoto's thyroiditis. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:2213-2217, 2018.

Isotretinoin as a Possible Environmental Trigger to Autoimmunity in Genetically Susceptible Patients.

Introduction. Isotretinoin is commonly used to treat cystic acne. Definitive mechanisms of action for isotretinoin are not known though despite many side effects having been documented. Various case reports have noted autoimmune diseases succeeding isotretinoin treatment. Case Report. A 16-year-old female presents with symptoms of tremors, lack of focus, sleeplessness, emotional liability, bulging eyes, loose stools, heat intolerance, and missed menstrual periods. Symptoms manifested shortly after the patient finished a course of oral isotretinoin treatment for acne. Physical exam showed resting tremors, bilateral proptosis, hyperactivity, and rapid speech. A diagnosis of Graves' Disease was made by correlating symptoms, physical exam findings, ultrasound, and positive family history of autoimmune thyroid disease. Conclusion. Emergence of autoimmune thyroid diseases depends upon genetic predisposition and environmental triggers. Mechanism of action for isotretinoin is not known but the drug may play a role in triggering autoimmunity in genetically susceptible individuals.

Effectiveness of Shared Medical Appointments Versus Traditional Clinic Visits for Adolescents With Type 1 Diabetes.

Shared medical appointments began in the United States in 1996 to advance quality of care and enhance patients' ability to self-manage. Group visits gather patients with the same diagnosis for individual examinations followed by group education sessions taught by the provider. This leads to the opportunity to learn from the experiences of others. The Cleveland Clinic Department of Pediatric Endocrinology offers a shared medical appointment group for pediatric patients with type 1 diabetes called the ESCALAIT clinic (Enrichment Services and Care for Adolescents Living with Autoimmune Insulin Dependent Type 1 Diabetes). The objective of this study was to compare the effectiveness of traditional clinic visits with shared medical appointments for adolescents with type 1 diabetes in terms of hemoglobin A1c (HbA1c) improvement. Eighty ESCALAIT patients, aged 11 to 19 years were compared with 516 clinic controls of the same age. Visits were approximately 3 months apart for both patient groups. Changes in HbA1c between groups were calculated from the first to fourth visits. There was a statistically significant difference between the ESCALAIT clinic patients and the control patients. Our results revealed that the group visit patients had less improvement in HbA1c values at the last visit approximately 1 year later, but we would argue that the difference is not clinically significant. However, there were many benefits to shared medical appointment visits including increased access to care as well as peer support. Shared medical appointments are therefore a valid alternative to traditional clinic visits in this patient population.

45,X/47,XXX Mosaicism and Short Stature.

We describe the case of a ten-year-old girl with short stature and 45,X/47,XXX genotype. She also suffered from vesicoureteric reflux and kidney dysfunction prior to having surgery on her ureters. Otherwise, she does not have any of the characteristics of Turner nor Triple X syndrome. It has been shown that this mosaic condition as well as other varieties creates a milder phenotype than typical Turner syndrome, which is what we mostly see in our patient. However, this patient is a special case, because she is exceptionally short. Overall, one cannot predict the resultant phenotype in these mosaic conditions. This creates difficulty in counseling parents whose children or fetuses have these karyotypes.

Menarchal timing in type 1 diabetes through the last 4 decades.

OBJECTIVE: We sought to examine whether age at menarche has changed over the past 4 decades by comparing age at menarche by year of diagnosis with type 1 diabetes. RESEARCH DESIGN AND METHODS: This work consisted of a cross-sectional study of age at menarche in two cohorts: adolescents (ages 11-24 years, n = 228) and adults (ages 19-55 years, n = 290, enrolled in the Coronary Artery Calcification in Type 1 Diabetes study). RESULTS: The adolescent cohort reported a younger age of menarche than the adult women with type 1 diabetes (12.69 ± 0.08 vs. 13.22 ± 0.12 years, mean ± SE, P < 0.001). Age at menarche was later in both adolescent girls and adult women with type 1 diabetes diagnosed before menarche (12.82 ± 1.16 and 13.7 ± 2.23 years) than for individuals diagnosed after menarche (12.12 ± 1.25 and 12.65 ± 1.38 years, P < 0.001 for both). Age at menarche was then examined by decade of type 1 diabetes diagnosis (1970-1979, 1980-1989, 1990-1999, and 2000-2009). Age at menarche significantly declined over the 4 decades (P = 0.0002). However, the delay in menarche among girls diagnosed with type 1 diabetes before menarche compared with those diagnosed after menarche was also significant across all decades (P < 0.0001) and did not change significantly over time (P = 0.41 for interaction of cohort and diagnosis premenarche). CONCLUSIONS: Age at menarche has declined over the past 4 decades among girls with type 1 diabetes, but a delay in age at menarche remains among individuals diagnosed before menarche compared with individuals diagnosed after menarche.

Physical activity in adolescent females with type 1 diabetes.

Objective. We sought to identify amount of physical activity and relationship of physical activity to glycemic control among adolescent females 11 to 19 years of age with type 1 diabetes mellitus (T1DM). We also sought to evaluate associations of age and ethnicity with physical activity levels. Research Design and Methods. Adolescent females ages 11-19 years (n = 203) were recruited during their outpatient diabetes appointment. Physical activity was obtained by self-report and was categorized as the number of days subjects had accumulated 60 minutes of moderate-to-vigorous physical activity during the past 7 days and for a typical week. Results. Girls reported being physically active for at least 60 minutes per day on 2.7 +/- 2.3 days in the last week, and on 3.1 +/- 2.2 days in a typical week. A greater number of physically active days in a typical week were associated with lower A1c (P = .049) in linear regression analysis. Conclusion. Adolescent females with T1DM report exercising for at least 60 minutes about 3 days per week, which does not meet the international recommendations of 60 minutes of moderate-to-vigorous activity per day. It is particularly important that adolescent girls with T1DM be encouraged to exercise since a greater number of physically active days per week is associated with better glycemic control.

Using the electronic medical record to improve education in patients at risk for adrenal insufficiency.

Background. Adrenal insufficiency is a life-threatening event. It is recommended that patients with known adrenal insufficiency and their families receive careful and repeated education on sick-day glucocorticoid management. We hypothesized that the electronic medical record (EMR) can be used to improve patient education through automated provider notification. Methods. We established an automated electronic alert in the EMR that triggered in the outpatient endocrine clinic. The alert asked if stress dose education was reviewed at the visit. The response to this alert was evaluated between July 15, 2009 and February 19, 2010. Results. 128 unique patients had visits both prior to and following the implementation of the EMR alert. The alert was acknowledged in 58 unique patient visits. After the alert was implemented, 87/128 (68%) of the patients had documentation in their record that stress dosing was reviewed. In the visit just prior to implementation of the alert, 48/128 (38%) of the patient encounters showed written documentation of stress dose review. Conclusion. This report documents that an automated alert in the EMR can promote improved provider adherence to recommendations regarding ongoing education of patients for stress dosing of glucocorticoids. Whether this translates into better outcomes for patients remains to be seen.