Obesity and Endocrine Management David R. Weber, MD, MSCE,a​ Stasia Hadjiyannakis, MD,b​ Hugh J. McMillan, MD, MSc,​b ofGarey Noritz,the MD,c​ LeannePatient M. Ward, MDb With Duchenne Muscular Dystrophy abstract

Duchenne muscular dystrophy (DMD) is associated with an increased risk of endocrine complications due to the effects of prolonged glucocorticoid therapy as well as progressive muscle weakness. Categories of complications include obesity and its comorbidities, short stature, pubertal delay, and adrenal insufficiency. Obesity prevention is important for long- term management of patients with DMD. Preventing glucocorticoid-induced weight gain fosters patient mobility, ease of transfer, and reduces sleep-disordered breathing. Metabolic complications from obesity (glucose intolerance, dyslipidemia) also can be avoided. Short stature and pubertal delay may negatively affect self-esteem and peer relationships, and careful monitoring of growth and pubertal development can allow anticipatory counseling. Adrenal insufficiency, a potentially life-threatening complication associated with prolonged glucocorticoid use, must be recognized so as to allow prompt treatment. In this article, we provide a summary of current guidance to ensure comprehensive endocrine management is followed in patients with DMD.

The effect of glucocorticoid therapy on the clinical phenotype in patients with Duchenne muscular dystrophy (DMD) has led to the need for clear recommendations about weight management

aGolisano Children’s Hospital, School of Medicine and Dentistry, University of Rochester, Rochester, New York; bDepartment of Pediatrics, Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada; and cNationwide Children’s Hospital, The Ohio State University, Columbus, Ohio

The guidelines or recommendations in this article are not American Academy of Pediatrics policy and publication herein does not imply endorsement.

Dr Ward served as chairperson for the Duchenne Muscular Dystrophy Care Considerations Endocrine and Bone Health Working Group, as convened by the Centers for Disease Control and Prevention, and drafted the initial outline for the manuscript; Drs Weber and Hadjiyannakis served on the Duchenne Muscular Dystrophy Care Considerations Endocrine and Bone Health Working Group, as convened by the Centers for Disease Control and Prevention, contributed to the development of corresponding recommendations, and drafted the initial manuscript; Drs McMillan and Noritz served on the Duchenne Muscular Dystrophy Care Considerations Endocrine and Bone Health Working Group, as convened by the Centers for Disease Control and Prevention, and contributed to the development of corresponding recommendations; and all authors reviewed and revised the manuscript, approved the final manuscript as submitted, and agree to be accountable for all aspects of the work. DOI: https://​doi.​org/​10.​1542/​peds.​2018-​0333F Accepted for publication Jul 26, 2018 Address correspondence to Leanne M. Ward, MD, Children’s Hospital of Eastern Ontario, University of Ottawa, 401 Smyth Rd, Ottawa, ON, K1H 8L1, Canada. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2018 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: Other than those listed under Potential Conflict of Interest; the other authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: Supported in part by the Cooperative Agreement, NU38OT000167, funded by the Centers for Disease Control and Prevention. Dr Ward was supported by a Research Chair from the University of Ottawa.

Downloaded from www.aappublications.org/news by guest on September 24, 2021 PEDIATRICS Volume 142, number s2, October 2018:e20180333F SUPPLEMENT ARTICLE and the monitoring and treatment expenditure due to limited options to guide effective obesity prevention of endocrine complications. for physical activity. Increased time and management strategies that can The appetite-promoting and fat and financial pressures for families feasiblyObesity Preventionbe implemented in their care. deposition effects of GC therapy with children who have special are prominent in this condition health care needs such as DMD also and perpetuate serious obesity- can contribute to risk of obesity Obesity prevention strategies related comorbidities such as and create barriers to2 successful should be introduced at 3 key time diabetes, dyslipidemia, and sleep weight management. Once weight points: (1) diagnosis, (2) time of apnea. Glucocorticoid therapy also is gained, biologic adaptations make glucocorticoid initiation, and (3) suppresses the hypothalamic and it extremely difficult to lose weight time of loss of mobility. Particular pituitary axes, causing an often and therefore3 prevention strategies attention should be given to patients profound linear growth failure are critical. In individuals with who have a family history of obesity, and marked delay in pubertal DMD, obesity can negatively affect given the highly hereditary nature z 10 ≥ development. The linear growth mobility and physical functioning, of obesity. An increase in weight failure of DMD is further affected by a resulting in falls and fractures; or BMI score of 0.511 also should direct adverse effect of glucocorticoid obesity can also exacerbate trigger intervention. therapy on growth plate function. the metabolic complications Glucocorticoid dependence due associated with glucocorticoid use. Obesity prevention strategies should to adrenal insufficiency is another Therefore, it is imperative that both aim to facilitate a healthy home food serious consequence of the high- obesity prevention strategies and environment of mostly whole foods, dose glucocorticoid therapy that is management are incorporated into regular and predictable times for typically prescribed in DMD. the care of individuals with DMD. meals and snacks that are mostly home prepared, family meals, limits All of these issues (obesity, growth on sugar-sweetened beverage Little research has been conducted failure, delayed puberty, and consumption and restaurant meals, in the area of obesity prevention adrenal insufficiency) can adversely and encouragement of screen-free or management strategies in DMD affect quality of life, and adequate meals and snacks at the table. This and in children with physical treatment of adrenal insufficiency should be done in consultation and developmental disabilities in in patients with glucocorticoid 4 with a dietitian. Obesity prevention general. Family-based behavioral dependence is a potential life- strategies also should include 1 interventions have shown modest saving measure. In this review, we counseling around appropriate sleep reduction in BMI in the short-term target pediatricians, neurologists, hygiene and duration, limitations for children and youth with obesity endocrinologists, and weight on screen time, and psychosocial in the absence of developmental management clinicians involved n 5,6​ assessments and support for both the and physical disabilities. ‍ One 12,13​ in the care of patients with DMD patients and their caregivers. ‍ small study ( = 3) on the treatment by providing specific guidance on of obesity in children with DMD Although physical activity is a clinical practice in these areas. that targeted parents revealed mainstay of obesity prevention With appropriate prevention and ’ inconsistent changes in body weight, strategies, the approach to physical treatment of glucocorticoid-related increases in children s perceived activity recommendations in patients comorbidities, it is anticipated that quality of life, and increases in with DMD is more measured, the need to withdraw glucocorticoid healthy foods available at home. and the role of physical activity therapy to treat the underlying 14 However, a larger randomized in DMD remains controversial. disease will be largely or wholly controlled trial (RCT) is needed to To avoid disuse atrophy and obviated. more effectively examine7 the efficacy other secondary complications of OVERWEIGHT, OBESITY, AND RELATED of such an approach. Two small inactivity, it is necessary that those COMORBIDITIES pharmacotherapeutic trials have 8been who are ambulatory or in the early conducted, one with metformin9 nonambulatory stage participate and the other with topimarate,​ in gentle functional strengthening Vulnerability to obesity is largely but there remains insufficient activity, including a combination driven by genetic, prenatal, evidence regarding the benefit and of swimming pool exercises and developmental, and psychosocial safety of these medications in this recreation-based exercises in the risk factors. In individuals with DMD, clinical context. Given the paucity of community. Swimming is highly this risk is increased further because evidence and research in this area, recommended from the early of glucocorticoid use, decreased the unique determinants of obesity in ambulatory to early nonambulatory mobility, and reduced energy individuals with DMD should be used phase and could be continued in the Downloaded from www.aappublications.org/news by guest on September 24, 2021 S44 WEBER et al Weight Management nonambulatory phase as long as it is (social worker, counselor, and/or medically safe. Additional benefits psychologist) who have training More intensive weight management might be provided by low-resistance z in motivational interviewing, strategies should be introduced strength training and optimization goal setting, monitoring, and if weight for age or BMI score of upper body function. Significant positive reinforcement techniques. is increased by >0.5 between muscle pain or myoglobulinuria in Interventions must be mindful of, visits and/or if BMI is >85th the 24-hour period after a specific and adapted to, the unique needs of percentile. A referral to an intensive activity is a sign of overexertion and the patient and family. More specific 15 interdisciplinary weight management “ that the activity should be modified. recommendations can be found Monitoring of Weight Status program or to a clinician with within the Recommendations for expertise in pediatric weight ” Treatment of Child and Adolescent management should be made if BMI 21 Overweight and Obesity. ‍ Practical is >85th percentile with associated clinical resources include The 5As of Monitoring weight status should weight-related health complications 22 Pediatric Obesity Management and include measuring body weight and and/or if BMI is >95th percentile. linear height in ambulatory patients the Healthy22 Active Living for Families or arm span and segmental length Evidence-based guidelines for MonitoringProgram. Weight-Related Health in nonambulatory patients at least managing obesity in individuals Complications every 6 months. Both BMI and weight with DMD or children with physical should be plotted on the appropriate and developmental4 disabilities do curve to determine the percentile for not currently exist ; therefore, an Metabolic complications of obesity age. Optimal weight status is defined adaptation of current clinical practice include glucose dysregulation, as BMI between the 10th and 85th guidelines for managing pediatric type 2 diabetes, dyslipidemia, percentiles. If height is unavailable or obesity, with the exception of and hypertension. The metabolic there are significant concerns about physical activity recommendations, complications of obesity are often its accuracy, weight for age can be should be applied. The principles of silent and need to be screened to used, and an appropriate weight gain weight management are in essence identify and manage them. Table trajectory as per the growth curve a more intensive application of 1 lists comorbidities for which can be anotherz indicator of optimal obesity prevention strategies regular monitoring and possible weight gain. An increase in weight for (as above). Family participation intervention are recommended. age or BMI scores by >0.5 between in lifestyle change is essential, Metabolic complications also are and interventions must include visits should raise concern11 and highly heritable, and a family history nutritional and psychosocial prompt intervention. should result in increased23 vigilance reassessment and support,6 with around screening. Glucocorticoid Although body composition is altered frequent follow-up. High-intensity use increases the risk of both obesity in individuals with DMD (lower lean programs (>25 hours of contact and its metabolic complications. body mass and higher fat mass), the with the child and/or family over Signs and symptoms of obesity- role of direct measurement of body a 6-month period) were able to induced biomechanical complications composition remains unclear and is demonstrate improvement in weight can typically be elicited on not routinely recommended. Direct status 12 months after beginning the 6 routine history and physical measures of adiposity have limited intervention. These interventions examination. Effective management accessibility in most clinical settings were focused on counseling and 16 of biomechanical complications, and are not sufficiently accurate. behavioral management techniques especially sleep apnea and sleep- Although reference data for a number to assist with implementation of disordered breathing, may help of pediatric dual-energy x-ray lifestyle change. Interventions – improve success with weight absorptiometry body composition may incorporate a structured daily 24 17 19 management. measures have been published,​ ‍ ‍ eating plan with the addition of it remains unclear what their clinical some self-monitoring (through the Children and youth with obesity are applicability will be both within and use of logs) under the supervision at increased risk of 25social isolation outside of the population with DMD. of a dietitian who has training in and stigmatization. Childhood Longitudinal data on the relation weight management, with careful psychiatric disorders (depression, of adiposity in children to future attention paid to avoid overly anxiety), school difficulties, body disease risk in adults also is lacking; restrictive dieting practices. dissatisfaction, dysregulated therefore, no agreement exists about Personnel should include a registered eating behaviors, teasing, and cut-points for excess adiposity20 that dietitian, physical activity expert, bullying have all been26,27​ linked with would constitute obesity. and mental health professional pediatric obesity. ‍ Mental health Downloaded from www.aappublications.org/news by guest on September 24, 2021 PEDIATRICS Volume 142, number s2, October 2018 S45 TABLE 1 Recommended Monitoring for Obesity-Related Comorbidities Recommended Monitoring Intervention Hyperglycemia History: polyuria, polydipsia Dietary assessment Annual random blood glucose and A1C Endocrine consultation if: symptomatic with random blood glucose If asymptomatic with random blood glucose ≥200 mg/dL (11.1 mmol/L) or 2 random blood glucose readings ≥11.1 mmol/L, repeat random blood glucose ≥200 mg/dL (11.1 mmol/L) in the absence of symptoms and/or A1C within 1 wk ≥6.5 (American Diabetes Association Clinical Practice Guidelines 2015) Hypertension Blood pressure should be monitored at each Dietary assessment clinic visit (minimum annually, ideally every Referral to hypertension clinic if blood pressure >95th% for height 6 mo) and sex on ≥3 occasions taken over wk to mo (Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents, NIH) Dyslipidemia Random lipid profile annually. If abnormal, Dietary assessment arrange for fasting lipid profile Refer to lipid clinic if LDL-C ≥160 mg/dL (4.2 mmol/L) and/or non- HDL-C ≥190 mg/dL (4.9 mmol/L) on ≥2 fasting lipid profiles done months apart23 Gastroesophageal reflux disease Inquire about GERD symptoms (heartburn); H2 blocker or proton pump inhibitors if symptomatic (2010 minimum annually, ideally every 6 mo guidelines) Obstructive sleep apnea and/or sleep Inquire about symptoms: morning headaches, Sleep study and referral to sleep clinic if abnormal disordered breathing daytime somnolence, change in mood, decreased ability to concentrate and/or focus (minimum annually, ideally every 6 mo) Mental health assessment Inquire about mood and anxiety symptoms, Referral to mental health professional (social worker, psychologist, disordered eating patterns, body image, and counselor) for further assessment and support school functioning GERD, gastroesophageal reflux disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; NIH, National Institutes of Health.

30,31​ 39 disorders, as well as some of the compared with reference data. ‍ compared with daily dosing. The pharmacotherapeutic agents that are The authors of a natural history mechanisms underlying the growth used to manage them, can complicate study reported that the median inhibitory effects of glucocorticoids weight management, promote height of participants at age 1832 years are complex. Glucocorticoid exposure weight gain, and affect prognosis was below the fifth percentile. appears40 to inhibit growth hormone and therefore should be routinely The etiology of the impaired growth release,​– antagonize the peripheral monitored28 through history at clinic in individuals with DMD remains action41 of 43growth hormone and visits. unclear because growth hormone IGF-1,​ ‍ and induce chondrocyte44 ENDOCRINE DISORDERS: SHORT secretion33 in response to provocative28 apoptosis at the growth plate. STATURE, PUBERTAL DELAY, AND testing,​ circulating growth29 factors,​ Growth should be verified every 6 ADRENAL INSUFFICIENCY and skeletal maturation were months in all patients with DMD normal in patients with DMD. until puberty has finished and final Growth Failure Causing Short 37 Growth impairment– in DMD is adult height has been reached. Stature exacerbated34 by36 glucocorticoid Standing height is acceptable for treatment. ‍ ‍ Current patients who are still walking, recommendations support the with the results compared with a Short stature is common in initiation of glucocorticoid therapy standardized growth curve. A DMD- ï ï individuals with DMD. Observational before functional decline; therefore, specific growth curve derived from studies of glucocorticoid-na ve, patients are exposed to the glucocorticoid-na ve patients is ambulatory patients with DMD have deleterious effects of glucocorticoid37 available for patients ages 2 to 12 described a growth pattern marked for the majority of their growth. years, although30 its clinical usefulness by (1) normal length at birth, (2) Glucocorticoid treatment regimens is untested. Growth is evaluated below-average growth velocity in vary and may affect growth differently in nonambulatory early life, and (3) age-appropriate differently. Growth impairment patients, ideally starting before loss growth velocity at a below-average was observed irrespective of of ambulation to permit tracking of height percentile28,29​ for the remainder of agent (prednisone, prednisolone, the growth rate during transition childhood. ‍ A study of ambulatory deflazacort)38 in a natural history from walking to nonambulatory. Arm patients with DMD revealed that study. However, an RCT revealed span, ulnar and tibia lengths, knee participants were shorter than that a weekend-only prednisone height, and segmental measurements expected for age by an average of 4.3 cm regimen resulted in greater growth of recumbent length have been Downloaded from www.aappublications.org/news by guest on September 24, 2021 S46 WEBER et al FIGURE 1 Assessments and interventions for impaired growth and delayed puberty in patients with DMD. (Reproduced with permission from Birnkrant DJ, Bushby K, Bann CM, et al; DMD Care Considerations Working Group. Diagnosis and management of Duchenne muscular dystrophy, an update, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management. Lancet Neurol. 2018;17[3]:258.)

TABLE 2 Recommended Biochemical and Radiographic Tests for the Evaluation of Impaired Growth 45 and Delayed Puberty in Individuals With DMD proposed. However, these methods Impaired growth at any age as defined by any of the following have not been specifically validated Downward crossing of height percentile in DMD. A finding of impaired growth Height velocity of <4 cm/y (downward crossing of percentile for Height less than third percentile height, height velocity <4 cm/year, Recommended To be considered a or height below the third percentile) Bone age radiograph of left hand Growth hormone stimulation testing Thyroid function testsb should prompt consultation with an Celiac panel endocrinologist. A standard clinical Growth factorsc evaluation should be performed in Comprehensive metabolic paneld all patients with DMD with growth Complete blood count failure to identify treatable hormonal Delayed puberty as defined by Testicular volume <4 cm3 at age 14 y or older or other causes (Fig 1, Table 2). Recommended To be considered The treatment of DMD-related short Luteinizing hormonee Bone age radiograph of left hand stature is controversial. Recombinant Follicular stimulating hormone a human growth hormone (rhGH) is Routine use of growth hormone in the treatment of impaired growth is not recommended. Stimulation testing should be performed on an individual basis only in patients in whom a compelling clinical case for the use of growth hormones commonly used to treat hypothalamic exists. and/or pituitary growth hormone b Thyrotropin and total or free thyroxine. c deficiency and a handful of other Insulin-like growth factor 1 and/or insulin-like growth factor binding protein 3. 46 d Sodium, potassium, chloride, bicarbonate, serum urea nitrogen, creatinine, calcium, albumin, alkaline phosphatase, and childhood conditions. To date, alanine- and aspartate-aminotransferase. no RCTs have been conducted to e Luteinizing hormone, follicular stimulating hormone, and testosterone should be checked at 8:00 am and assessed by evaluate the efficacy and safety using appropriate pediatric or ultrasensitive assay. of rhGH to improve growth in individuals with DMD. The only RCT of rhGH conducted in this population 40 47 was designed to investigate cardiac outcomes were reported. The 5.2 cm/year over 12 months. outcomes. The researchers found largest report of clinical rhGH use No detrimental musculoskeletal or that rhGH was well tolerated and in individuals with DMD included pulmonary effects were observed, that left ventricular mass increased 39 boys and revealed that growth although 3 boys developed known with treatment. However, no height velocity increased from 1.3 to rhGH-related adverse events Downloaded from www.aappublications.org/news by guest on September 24, 2021 PEDIATRICS Volume 142, number s2, October 2018 S47 TABLE 3 Example Testosterone Replacement Regimens in DMD Patients With Confirmed Hypogonadism Formulationa Dose Titrationb Intramuscular Testosterone enanthate or cypionate Initiate at 50 mg once monthly Increase dose by 50 mg every 3–6 mo over a period of 2–3 y Typical adult regimens include 150–200 mg every 2 wk or 75–150 mg every wk Serum testosterone levels should be monitored every 3–6 mo Target testosterone levels (drawn 1 wk after injection) in the midnormal range (350–750 ng/dL [12–26 nmol/L]) Transdermal Gels (pumps or packets) Initiate at lowest possible daily dose given formulation 1% gel (12.5–50 mg per application) Increase dose gradually every 3–6 mo over a period of 2–3 y 1.62% gel (20.25–40.5 mg per application) Typical adult regimens range from 20.25 to 100 mg daily based on formulation 2% gel (10 mg per application) Serum testosterone levels should be monitored every 3–6 mo Target testosterone levels (drawn any time) in the midnormal range (350–750 ng/dL [12–26 nmol/L]) Patch Not commonly used to initiate puberty 2–4 mg per patch applied daily May be a convenient option for some patients once typical adult replacement levels have been achieved Typical adult regimens range from 2 to 4 mg daily Serum testosterone levels should be monitored every 3 to 6 mo Target testosterone levels (drawn 3–12 h after patch placed) in the midnormal range (350–750 ng/dL [12–26 nmol/L]) a Other testosterone formulations may be available depending on country. Consult prescribing information provided by manufacturer for recommended dosing. b Adult dosing and monitoring recommendations adapted from the Endocrine Society Clinical Practice Guideline for testosterone therapy in adult men with androgen deficiency syndromes.58

(impaired fasting glucose, worsening health, psychosocial development, 2 to 3 years until adult testosterone of scoliosis, and benign intracranial and self-esteem. Studies have levels are achieved. Examples hypertension). Adding to the revealed that pubertal delay in of commonly used testosterone controversy are theoretical concerns individuals with DMD is common, regimens are provided in Table 3. that increased growth may worsen48,49​ with a prevalence of 50% to 100%55,56​ Patients and families should be muscle function in this context. in glucocorticoid-treated boys. ‍ counseled about expected effects, The relevance of this evidence to No published RCTs have contained including body odor, facial hair, acne, humans remains uncertain, however, assessments of the safety and efficacy growth spurt, growth plate closure, and clinical trials investigating of testosterone to induce puberty in and increased libido. Testosterone the use of mazindol, a postulated individuals with DMD. However, the levels should be monitored to inhibitor of growth hormone release, authors of a retrospective study of adjust dose. Annual monitoring yielded inconsistent effects– on 14 boys treated with testosterone of hemoglobin and/or hematocrit, growth suppression33, and50​ 53no benefits reported patient satisfaction with lipids, and serum58 glucose should on muscle strength. ‍ ‍ In light treatment and increased growth 57 be considered. An unexpected of limited data and the ongoing velocity in the first year of therapy. adverse effect on muscle or cardiac controversy, regular use of rhGH Testosterone is widely used in health may warrant discontinuation in the population with DMD is not pediatrics to induce puberty and or dose reduction. recommended. The decision to use is specifically advised in treatment Currently, the expected benefit rhGH should be made on a case-by- of adult men with glucocorticoid- 58 of restoring testosterone to case basis with biochemical evidence induced hypogonadism. normal physiologic levels is felt of growth hormone deficiency, and to outweigh potential risks of after a discussion of the benefits All patients with DMD should treatment. However, future studies and known plus unknown risks. For undergo monitoring of pubertal are needed to identify the optimal example, it is unknown whether development by physical timing and regimen for testosterone rhGH adversely affects muscle examination every 6 months37 starting replacement in individuals with DMD. strength. at age 9 years (Fig 1). A finding Glucocorticoid Dependence and Delayed Pubertal Development ≥ Adrenal Insufficiency of delayed puberty (absence of3 testicular enlargement 4 cm by age 14 years) should prompt referral Delayed or absent pubertal to an endocrinologist. Testosterone Chronic glucocorticoid therapy at the development in glucocorticoid- is recommended starting by age doses used on individuals with DMD treated patients with DMD is due to54 14 years (or by 12 years in those on leads to a suppressed hypothalamic- hypogonadotropic hypogonadism glucocorticoids) at a low dose and pituitary-adrenal (HPA) axis. and may negatively affect physical should be increased gradually over Patients are therefore at risk for Downloaded from www.aappublications.org/news by guest on September 24, 2021 S48 WEBER et al TABLE 4 Management of Adrenal Suppression in Patients on Chronic Glucocorticoid Therapy Stress Situation Stress Dosing Recommendations Mild 25 mg/m2 per da hydrocortisone or equivalentb divided every 6–8 h PO Mild febrile illness Continue for 24 h after return to baseline health Minor surgical procedure requiring anesthesia Moderate 50 mg/m2 per d hydrocortisone or Eq divided every 6–8 h PO, IM, or IV Moderate illness requiring hospital admission Consider taper as clinical condition improves Major elective surgery requiring anesthesia Severe 100 mg/m2 hydrocortisone IM or IV followed by Severe vomiting, loss of consciousness 100 mg/m2 per d hydrocortisone divided every 4–6 h IV Septic shock Consider taper as clinical condition improves Severe trauma or illness requiring emergent surgery Example steroid taperc Decrease prednisone and/or deflazacort dose by 20%–25% every 2 wk Once physiologic dose is achieved (3 mg/m2 per d of prednisone and/or deflazacort) switch to hydrocortisone 12 mg/m2 per d divided in 3 equal doses Continue to wean dose by 20%–25% every 2 wk until a dose of 2.5 mg hydrocortisone every other d is achieved After 2 wk of every other d dosing, discontinue hydrocortisone Periodically check am cortisol or CRH and/or corticotropin stimulated cortisol level until HPA axis is determined to be normald Continue stress dose coverage until HPA axis has recovered. This may take up to 12 mo or longer AM, morning; CRH, corticorelin; IM, intramuscular; IV, intravenous; PO, per os (oral). a Doses expressed in terms of milligram per body surface area (in meters2). b Or equivalent. Multiply prednisone dose (milligram) by 4 to convert to hydrocortisone equivalents (milligram). Many patients on standard prednisone regimens will not require supplemental hydrocortisone for mild or moderate stress if able to continue usual home doses. c Adapted from Parent Project Muscular Dystrophy.1 d Adequate cortisol response to CRH or ACTH stimulation (peak cortisol >20 μg/dL [550 nmol/L]).

life-threatening adrenal crisis should guidance: (1) gradual dose reduction; discontinuation of daily physiologic glucocorticoid therapy be stopped (2) monitoring for signs and/or steroid therapy, an expert in adrenal suddenly and also during times of symptoms of adrenal insufficiency suppression management should 59 am’ severe injury or illness. All patients (fatigue, headache, nausea and/or interpret the 8:00 cortisol results on glucocorticoids should be taught vomiting, hypoglycemia, in light of the child s clinical status the symptoms, signs, and appropriate hypotension); (3) dose increase and and in accordance with local practice management of adrenal crisis at slowing of taper in response to signs standards. These decisions are the time of initial glucocorticoid or symptoms; and (4) continuation of typically made in collaboration with prescription, including intramuscular stress steroid coverage until the taper an endocrinologist. A protocol for the hydrocortisone administrative for is complete and the HPA axis has management of adrenal suppression64 home use in the event the patient been proven normal by an adequate has been developed previously cannot take his usual glucocorticoid cortisol response to corticorelin and endorsed by the DMD Care μ Considerations Working Group. therapy because of vomiting. Patient or corticotropin stimulation (peak60 education should also include cortisol >20 g/dL [550 nmol/L]). CONCLUSIONS emergency administration of HPA axis61, recovery62​ can take months intramuscular hydrocortisone and to years. Periodic monitoring of am μ instructions for stress dosing during 8:00 cortisol levels for a return to Because of the positive effects times of illness, trauma, or surgical a normal 63value (eg, >6 g/dL [165 of glucocorticoid therapy on intervention (Table 4). The need nmol/L]) can guide the decision ambulation, mitigation of scoliosis, for education around intramuscular around when to discontinue daily and cardiorespiratory function in hydrocortisone is testament to the steroid therapy and to perform individuals with DMD, glucocorticoid potentially life-threatening nature stimulation testing, recognizing therapy has been widely adopted of adrenal suppression in the face of that the precise threshold that is as the standard of care for pediatric am illness and surgery. Glucocorticoid used to define a normal 8:00 and adult patients with DMD. At the therapy is never discontinued cortisol may vary depending same time, the adverse effects of abruptly, but rather tapered slowly on institution-specific practice glucocorticoid therapy on weight to allow HPA recovery. A steroid standards. Irrespective of the specific management and the hormonal taper should adhere to the following threshold that is used to signal milieu are often troubling for patients Downloaded from www.aappublications.org/news by guest on September 24, 2021 PEDIATRICS Volume 142, number s2, October 2018 S49 and in some cases are potentially managing these important side Institute, the University of Ottawa ’ life-threatening (in the case of effects should not be viewed as Research Chair Program, and the glucocorticoid-dependence and optional but rather a mandatory Children s Hospital of Eastern adrenal insufficiency). To maintain component of the approach to Ontario Departments of Pediatrics a positive benefit-to-toxicity ratio, glucocorticoid therapy in this setting. and Surgery. glucocorticoid therapy to treat ACKNOWLEDGMENTS ABBREVIATIONS the underlying disease should be integrated with clinical programs that effectively address the resulting We thank Victor Konji for his DMD: Duchenne muscular side effects. In most cases, this will assistance in the preparation of dystrophy require a multidisciplinary effort, references for the manuscript. Dr HPA: hypothalamic-pituitary- with input from neuromuscular Leanne M. Ward was supported by adrenal specialists, endocrinologists, the Canadian Institutions for Health RCT: randomized controlled trial primary health care providers, and Research Operating Grants Program, ’ rhGH: recombinant human clinicians with expertise in obesity the Canadian Child Health Clinician growth hormone management. A comprehensive Scientist Program, the Children s approach to monitoring and Hospital of Eastern Ontario Research POTENTIAL CONFLICT OF INTEREST: Dr Weber has previously served as a paid consultant for Marathon Pharmaceuticals; Drs Ward, Hadjiyannakis, McMillan, and Noritz have indicated they have no potential conflicts of interest to disclose.

REFERENCES 1. Kinnett K, Noritz G. The PJ Nicholoff 7. Arikian A, Boutelle K, Peterson CB, report. Pediatrics. 2007;120(suppl 4): steroid protocol for Duchenne Dalton J, Day JW, Crow SJ. Targeting S164–S192 and Becker muscular dystrophy parents for the treatment of pediatric 13. T remblay MS, Carson V, Chaput JP, and adrenal suppression. PLoS obesity in boys with Duchenne et al. Canadian 24-hour movement Curr. 2017;9:ecurrents.​md.d18deef​ muscular dystrophy: a case series. Eat guidelines for children and youth: 7dac96ed13​5e0dc87399​17b6e Weight Disord. 2010;15(3):e161 e165 – an integration of physical activity, 2. Must A, Curtin C, Hubbard K, Sikich 8. Casteels K, Fieuws S, van Helvoirt M, sedentary behaviour, and sleep. L, Bedford J, Bandini L. Obesity et al. Metformin therapy to reduce Appl Physiol Nutr Metab. 2016; prevention for children with weight gain and visceral adiposity 41(6 suppl 3):S311–S327 developmental disabilities. Curr Obes in children and adolescents with 14. Marker t CD, Ambrosio F, Call JA, Rep. 2014;3(2):156–170 neurogenic or myogenic motor deficit. Grange RW. Exercise and Duchenne Pediatr Diabetes. 2010;11(1):61–69 muscular dystrophy: toward evidence- 3. Schwar tz AV. Diabetes mellitus: based exercise prescription. Muscle does it affect bone? Calcif Tissue Int. 9. Car ter GT, Yudkowsky MP, Han Nerve. 2011;43(4):464–478 2003;73(6):515–519 JJ, McCrory MA. Topiramate for weight reduction in Duchenne 15. Bushby K, Finkel R, Birnkrant DJ, et al; 4. Bandini L, Danielson M, Esposito muscular dystrophy. Muscle Nerve. DMD Care Considerations Working LE, et al. Obesity in children with 2005;31(6):788–789 Group. Diagnosis and management of developmental and/or physical Duchenne muscular dystrophy, part disabilities. Disabil Health J. 10. Farooqi S, O’Rahilly S. Genetics of 2: implementation of multidisciplinary 2015;8(3):309–316 obesity in humans. Endocr Rev. 2006; care. Lancet Neurol. 2010;9(2):177–189 27(7):710–718 5. Vincent C, Gagnon D, Routhier F, et al; 16. Wells JC, Fewtrell MS. Measuring ADMI Group. Service dogs in the 11. Ford AL, Hunt LP, Cooper A, Shield body composition. Arch Dis Child. province of Quebec: sociodemographic JP. What reduction in BMI SDS is 2006;91(7):612–617 profile of users and the dogs’ impact required in obese adolescents to 17. Ogden CL, Li Y, Freedman DS, Borrud on functional ability. Disabil Rehabil improve body composition and LG, Flegal KM. Smoothed percentage Assist Technol. 2015;10(2):132–140 cardiometabolic health? Arch Dis Child. body fat percentiles for U.S. children 2010;95(4):256–261 and adolescents, 1999-2004. Natl 6. Bar ton M; US Preventive Services Health Stat Rep. 2011;(43):1 7 Task Force. Screening for obesity 12. Barlow SE; Expert Committee. Expert – in children and adolescents: US committee recommendations 18. Wells JC, Williams JE, Chomtho S, et al. Preventive Services Task Force regarding the prevention, assessment, Body-composition reference data recommendation statement. and treatment of child and adolescent for simple and reference techniques Pediatrics. 2010;125(2):361–367 overweight and obesity: summary and a 4-component model: a new

Downloaded from www.aappublications.org/news by guest on September 24, 2021 S50 WEBER et al UK reference child. Am J Clin Nutr. dystrophy: a study of 34 patients. Acta Natural History Study. Neurology. 2012;96(6):1316–1326 Paediatr. 1999;88(1):62–65 2015;85(12):1048–1055 19. Weber DR, Moore RH, Leonard MB, 29. Eiholzer U, Boltshauser E, Frey D, 39. Escolar DM, Hache LP, Clemens PR, Zemel BS. Fat and lean BMI reference Molinari L, Zachmann M. Short stature: et al. Randomized, blinded trial of curves in children and adolescents a common feature in Duchenne weekend vs daily prednisone in and their utility in identifying excess muscular dystrophy. Eur J Pediatr. Duchenne muscular dystrophy. adiposity compared with BMI and 1988;147(6):602–605 Neurology. 2011;77(5):444–452 percentage body fat. Am J Clin Nutr. 30. West NA, Yang ML, Weitzenkamp DA, 40. Cittadini A, Ines Comi L, Longobardi S, 2013;98(1):49–56 et al. Patterns of growth in ambulatory et al. A preliminary randomized study 20. Freedman DS, Sherry B. The validity males with Duchenne muscular of growth hormone administration of BMI as an indicator of body fatness dystrophy. J Pediatr. 2013;163(6): in Becker and Duchenne muscular and risk among children. Pediatrics. 1759–1763.e1 dystrophies. Eur Heart J. 2009;124(suppl 1):S23–S34 2003;24(7):664–672 31. Kuczmarski RJ, Ogden CL, Guo SS, et al. 21. Spear BA, Barlow SE, Ervin C, et al. 2000 CDC growth charts for the United 41. Wehrenber g WB, Janowski BA, Piering Recommendations for treatment States: methods and development. AW, Culler F, Jones KL. Glucocorticoids: of child and adolescent overweight potent inhibitors and stimulators Vital Health Stat 11. 2002;(246):1–190 and obesity. Pediatrics. 2007; of growth hormone secretion. 120(suppl 4):S254–S288 32. McDonald CM, Abresch RT, Carter GT, Endocrinology. 1990;126(6):3200–3203 et al. Profiles of neuromuscular 42. Allen DB, Julius JR, Breen TJ, Attie 22. American Academy of Pediatrics. diseases. Duchenne muscular KM. Treatment of glucocorticoid- Healthy Active Living for Families dystrophy. Am J Phys Med Rehabil. (HALF) program. 2016. Available at: induced growth suppression with 1995;74(suppl 5):S70–S92 https://​www.​aap.​org/​en-​us/​advocacy-​ growth hormone. National Cooperative and-​policy/​aap-​health-​initiatives/​HALF-​ 33. Zatz M, Rapaport D, Vainzof M, et al. Growth Study. J Clin Endocrinol Metab. Implementation-​Guide/​Pages/​About-​ Effect of mazindol on growth hormone 1998;83(8):2824–2829 levels in patients with Duchenne HALF.aspx.​ Accessed July 20, 2016 43. Jux C, Leiber K, H gel U, et al. muscular dystrophy. Am J Med Genet. ü 23. Exper t Panel on Integrated Guidelines Dexamethasone impairs growth 1988;31(4):821 833 for Cardiovascular Health and Risk – hormone (GH)-stimulated growth Reduction in Children and Adolescents; 34. Biggar WD, Harris VA, Eliasoph L, by suppression of local insulin-like National Heart, Lung, and Blood Alman B. Long-term benefits of growth factor (IGF)-I production and Institute. Expert panel on integrated deflazacort treatment for boys with expression of GH- and IGF-I-receptor guidelines for cardiovascular Duchenne muscular dystrophy in their in cultured rat chondrocytes. health and risk reduction in second decade. Neuromuscul Disord. Endocrinology. 1998;139(7):3296–3305 children and adolescents: summary 2006;16(4):249 255 – 44. Chrysis D, Ritzen EM, Sävendahl report. Pediatrics. 2011;128(suppl 35. Houde S, Filiatrault M, Fournier A, et al. L. Growth retardation induced by 5):S213 S256 – Deflazacort use in Duchenne muscular dexamethasone is associated with 24. Harsch IA, Konturek PC, Koebnick C, dystrophy: an 8-year follow-up. Pediatr increased apoptosis of the growth et al. Leptin and ghrelin levels in Neurol. 2008;38(3):200–206 plate chondrocytes. J Endocrinol. patients with obstructive sleep apnoea: 2003;176(3):331–337 effect of CPAP treatment. Eur Respir J. 36. Moxley RT III, Pandya S, Ciafaloni E, Fox DJ, Campbell K. Change 45. Lohman TG, Roche AF, Martorell R, 2003;22(2):251–257 in natural history of Duchenne eds. Anthropometric Standardization 25. Puhl RM, Latner JD. Stigma, obesity, muscular dystrophy with long-term Reference Manual. Champaign, IL: and the health of the nation’s children. corticosteroid treatment: implications Human Kinetics Books; 1988 Psychol Bull. 2007;133(4):557–580 for management. J Child Neurol. 46. Hardin DS, Kemp SF, Allen DB. Twenty 26. Gonzalez A, Boyle MH, Georgiades K, 2010;25(9):1116–1129 years of recombinant human growth Duncan L, Atkinson LR, MacMillan HL. 37. Birnkrant DJ, Bushby K, Bann CM, et al; hormone in children: relevance to Childhood and family influences on DMD Care Considerations Working pediatric care providers. Clin Pediatr body mass index in early adulthood: Group. Diagnosis and management of (Phila). 2007;46(4):279–286 findings from the Ontario Child Health Duchenne muscular dystrophy, part 2: 47. Rutter MM, Collins J, Rose SR, et al. Study. BMC Public Health. 2012;12:755 respiratory, cardiac, bone health, Growth hormone treatment in boys 27. Russell-Mayhew S, McVey G, Bardick A, and orthopaedic management. with Duchenne muscular dystrophy Ireland A. Mental health, wellness, and Lancet Neurol. 2018;17(4):347–361 and glucocorticoid-induced growth failure. Neuromuscul Disord. childhood overweight/obesity. J Obes. 38. Bello L, Gordish-Dressman H, 2012;22(12):1046 1056 2012;2012:281801 Morgenroth LP, et al; CINRG – 28. Nagel BH, Mortier W, Elmlinger M, Investigators. Prednisone/ 48. Zatz M, Rapaport D, Vainzof M, Wollmann HA, Schmitt K, Ranke MB. prednisolone and deflazacort et al. Relation between height Short stature in Duchenne muscular regimens in the CINRG Duchenne and clinical course in Duchenne

Downloaded from www.aappublications.org/news by guest on September 24, 2021 PEDIATRICS Volume 142, number s2, October 2018 S51 muscular dystrophy. Am J Med Genet. 54. Rosen H, Jameel ML, Barkan still a cause of morbidity and death 1988;29(2):405–410 AL. Dexamethasone suppresses in childhood. Pediatrics. 2007;119(2). 49. Bodor M, McDonald CM. Why short gonadotropin-releasing hormone Available at: www.​pediatrics.​org/​cgi/​ stature is beneficial in Duchenne (GnRH) secretion and has direct content/​full/​119/​2/​e484 muscular dystrophy. Muscle Nerve. pituitary effects in male rats: 60. Puar TH, Stikkelbroeck NM, Smans differential regulation of GnRH 2013;48(3):336–342 LC, Zelissen PM, Hermus AR. Adrenal receptor and gonadotropin crisis: still a deadly event in the 21st 50. Coakley JH, Moorcraft J, Hipkin LJ, responses to GnRH. Endocrinology. Smith CS, Griffiths RD, Edwards RH. century. Am J Med. 2016;129(3):339. 1988;122(6):2873–2880 The effect of mazindol on growth e1–339.e9 hormone secretion in boys with 55. Merlini L, Gennari M, Malaspina E, 61. Huber BM, Bolt IB, Sauvain MJ, et al. Early corticosteroid treatment Duchenne muscular dystrophy. Flück CE. Adrenal insufficiency J Neurol Neurosurg Psychiatry. in 4 Duchenne muscular dystrophy after glucocorticoid withdrawal patients: 14-year follow-up. Muscle 1988;51(12):1551–1557 in children with rheumatic Nerve. 2012;45(6):796–802 51. Zatz M, Rapaport D, Pavanello RC, diseases. Acta Paediatr. 2010; Rocha JM, Vainzof M, Nicolau W. 56. Dooley JM, Bobbitt SA, Cummings EA. 99(12):1889–1893 Nocturnal rhythm of growth hormone The impact of deflazacort on puberty in 62. Jamilloux Y, Liozon E, Pugnet G, et al. in Duchenne patients: effect of Duchenne muscular dystrophy. Pediatr Recovery of adrenal function after different doses of mazindol and/ Neurol. 2013;49(4):292–293 long-term glucocorticoid therapy for or cyproheptadine. Am J Med Genet. 57. Wood CL, Cheetham TD, Guglieri M, et al. giant cell arteritis: a cohort study. 1989;33(4):457–467 Testosterone treatment of pubertal PLoS One. 2013;8(7):e68713 52. Collipp PJ, Kelemen J, Chen SY, delay in Duchenne muscular dystrophy. 63. Charmandari E, Nicolaides NC, Castro-Magana M, Angulo M, Neuropediatrics. 2015;46(6):371–376 Chrousos GP. Adrenal insufficiency. Derenoncourt A. Growth hormone 58. Bhasin S, Cunningham GR, Hayes FJ, Lancet. 2014;383(9935):2152–2167 inhibition causes increased et al; Task Force, Endocrine Society. 64. Birnkrant DJ, Bushby K, Bann CM, et al; selenium levels in Duchenne Testosterone therapy in men with DMD Care Considerations Working muscular dystrophy: a possible new androgen deficiency syndromes: an Group. Diagnosis and management approach to therapy. J Med Genet. Endocrine Society clinical practice of Duchenne muscular dystrophy, 1984;21(4):254–256 guideline. J Clin Endocrinol Metab. part 1: diagnosis, and neuromuscular, 53. Griggs RC, Moxley RT III, Mendell JR, 2010;95(6):2536–2559 rehabilitation, endocrine, and et al. Randomized, double-blind trial 59. Shulman DI, Palmert MR, Kemp SF; gastrointestinal and nutritional of mazindol in Duchenne dystrophy. Lawson Wilkins Drug and Therapeutics management. Lancet Neurol. 2018; Muscle Nerve. 1990;13(12):1169–1173 Committee. Adrenal insufficiency: 17(3):251–267

Downloaded from www.aappublications.org/news by guest on September 24, 2021 S52 WEBER et al Obesity and Endocrine Management of the Patient With Duchenne Muscular Dystrophy David R. Weber, Stasia Hadjiyannakis, Hugh J. McMillan, Garey Noritz and Leanne M. Ward Pediatrics 2018;142;S43 DOI: 10.1542/peds.2018-0333F

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Downloaded from www.aappublications.org/news by guest on September 24, 2021 Obesity and Endocrine Management of the Patient With Duchenne Muscular Dystrophy David R. Weber, Stasia Hadjiyannakis, Hugh J. McMillan, Garey Noritz and Leanne M. Ward Pediatrics 2018;142;S43 DOI: 10.1542/peds.2018-0333F

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