Dexamethasone Therapy of Congenital Adrenal Hyperplasia and the Myth of the “Growth Toxic” Glucocorticoid

The use of long-acting glucocorticoids in the treatment of individuals with Congenital Adrenal Hyperplasia (CAH) has been greeted with controversy. Avoidance of dexamethasone therapy is in part due to the mistaken assumptions that dexamethasone is 30-fold more potent than hydrocortisone in suppressing adrenal activity, resulting in the overtreatment and the “growth toxic” label. However, as shown more than 50 years ago, dexamethasone is 80- to 100-fold (or greater) more potent than hydrocortisone in suppressing adrenal androgen production. When children are treated with low doses of dexamethasone once daily in the morning (0.15–0.3 mg/m2/day of dexamethasone versus 10–25 mg/m2/day of hydrocortisone), studies involving infants and children show that normal growth and skeletal maturation can be achieved, along with appropriate suppression of adrenal androgen secretion. Due to its high potency, the potential for overtreatment remains high with dexamethasone. Thus, it is imperative that dexamethasone-treated children be closely monitored

63 Years and 715 Days to the “Boxed Warning”: Unmasking of the Propylthiouracil Problem

715 days after potential problems related to PTU use in children were presented in a debate in front of the Lawson Wilkins Pediatric Endocrine Society (LWPES), the US Food and Drug Administration issued a “black-box” warning about the hepatotoxicity risk of the antithyroid drug propylthiouracil (PTU). This safety advisory followed the collective actions of academic societies, medical publishers, the National Institutes of Health, and the FDA. Considering that surgery and radioactive iodine are the legitimate treatment options for Grave Disease (GD), and are now the preferred alternative therapy in individuals who developed toxic reactions to MMI, the use of PTU should now be limited to exceptional circumstances and pregnancy. Long-term PTU therapy, especially in children, is not justifiable. The current advisory comes 63 years after the introduction of PTU for clinical use in 1947

Low-Dose Dexamethasone Therapy from Infancy of Virilizing Congenital Adrenal Hyperplasia

Objective. To assess the growth and control of adrenal androgen secretion in children with virilizing congenital adrenal hyperplasia (CAH) treated with dexamethasone. Method. We examined doses used, control of adrenal androgen secretion, and growth and skeletal maturation of 8 children with CAH treated with dexamethasone beginning in infancy. Results. 3 boys and 5 girls with classical CAH (17-hydroxyprogesterone at diagnosis >20,000 ng/dL) were treated with dexamethasone beginning at diagnosis (<10 days of age). Patients were also treated with fludrocortisone and sodium chloride. The average initial medication dose was 0.1 mg (0.28 ± 0.015 mg/m2); all doses were given in the morning using a dosing syringe to administer a 0.1 mg/mL elixir. The children were treated for 6.5 ± 2.0 years over which time the change in bone age to chronological age ratio (ΔBA/ΔCA) was 0.9 ± 0.06. Most recent height Z' scores were +0.5 ± 0.2, and body mass index (BMI) scores were 18 ± 0.2. Late afternoon levels of 17-hydroxyprogesterone, androstenedione, and testosterone were 780 ± 238 ng/dL (23.4 ± 7 nmol/L), 42 ± 10 ng/dL (1.4 ± 0.3 nmol/L), and 11.5 ± 3 ng/dL; (0.4 ± 0.1 nmol/L), respectively. Conclusions. These observations show that low doses of dexamethasone can be used to effectively treat CAH beginning in infancy

Prenatal Virilization Associated with Paternal Testosterone Gel Therapy

Transdermal testosterone gels are used in the treatment of hypoandrogenism of males. Virilization due to exposure to testosterone gels has been reported in children resulting in a US Food and Drug Administration (FDA) warning about secondary exposure to these products. At present, we are unaware of prenatal virilization associated with unintentional testosterone gel exposure. We report prenatal virilization in a female infant due to secondary maternal exposure to the father's testosterone gel. We also describe postnatal virilization of the child's twin sister

Propylthiouracil (PTU) Hepatoxicity in Children and Recommendations for Discontinuation of Use

Propylthiouracil (PTU) was introduced for clinical use in July 1947 for Graves' disease (GD) treatment. Over the 60 years that this medication has been used, reports of PTU-related liver failure and death have accumulated. On October 28, 2008, an expert panel evaluated PTU drug safety in children at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) It is estimated that about 4000 pediatric patients per year with GD are being treated with antithyroid drugs (ATDs) in the United States, and up to 30% of pediatric patients with GD are being treated with PTU. The risk of severe PTU-induced liver failure is estimated as 1 in 2000–4000 children. The number of children developing reversible PTU-induced liver injury is estimated to be at least 1 in 200. Routine biochemical surveillance of liver function and hepatocellular integrity is not useful in identifying children who will develop liver failure. Children appear to be at higher risk for PTU-induced liver injury than adults. PTU should not be used as first line therapy for the treatment of GD in children. Current PTU use in children taking this medication should be stopped in favor of alternate therapies

Adverse Events Associated with Methimazole Therapy of Graves' Disease in Children

Objective. Graves' disease is the most common cause of hyperthyroidism in the pediatric population. Antithyroid medications used in children and adults include propylthiouracil (PTU) and methimazole (MMI). At our center we have routinely used MMI for Graves' disease therapy. Our goals are to provide insights into adverse events that can be associated with MMI use. Methods. We reviewed the adverse events associated with MMI use in our last one hundred consecutive pediatric patients treated with this medication. Results. The range in the patient age was 3.5 to 18 years. The patients were treated with an average daily dose of MMI of 0.3±0.2 mg/kg/day. Adverse events attributed to the use of the medication were seen in 19 patients at 17±7 weeks of therapy. The most common side effects included pruritus and hives, which were seen in 8 patients. Three patients developed diffuse arthralgia and joint pain. Two patients developed neutropenia. Three patients developed Stevens-Johnson syndrome, requiring hospitalization in 1 child. Cholestatic jaundice was observed in 1 patient. No specific risk-factors for the development of adverse events were identified. Conclusions. MMI use in children is associated with a low but real risk of minor and major side effects

How do paediatricians use and monitor antithyroid drugs in the UK? A clinician survey

Objective We aimed to document current practice in the medical management of paediatric hyperthyroidism in the UK and compare to international recommendations. Design A 27‐question online survey distributed via an electronic newsletter in August 2018. Participants Responses from 48 members (11%) of the British Society for Paediatric Endocrinology and Diabetes. Measurements Information about antithyroid drug (ATD) preference, treatment duration, monitoring of full blood count (FBC), management of neutropaenia, agranulocytosis screening and patient education. Results Carbimazole is favoured by 98% of respondents and a “dose titration” regimen preferred over “block and replace” (65% vs 29%). TRAbs (thyroid‐stimulating hormone receptor antibodies) are used for diagnostic purposes by 85% and by 33% to look for evidence of disease remission. The majority (81%) treat for a minimum of 2 years before considering a trial off ATD. All respondents reported that they “always/usually” warn their patients about the risk of agranulocytosis before starting ATD, but written information is “rarely/never” provided by 63%. Sore throat (98%) and fever (92%) are the most commonly cited symptoms used to alert a patient to possible agranulocytosis. FBC is measured prior to treatment by 65% and measured periodically during treatment by 70%. Conclusions The management of paediatric hyperthyroidism with ATDs in the UK is not consistent with all international recommendations because a block and replace ATD regimen remains widely used. TRAbs are utilized at presentation, but underused for detecting disease remission. National consensus guidelines and written patient information may refine the management of paediatric patients on ATDs