Supplemental Appendix: Congenital Adrenal Hyperplasia Emergency Letter

Transcription

1 Supplemental Appendix: Congenital Adrenal Hyperplasia Emergency Letter 535 Bunker Hill Road, POBox 128, Strasburg, PA17579 T F EMERGENCY MANAGEMENT OF CONGENITAL ADRENAL HYPERPLASIA Patient: Jane Doe (DOB xx/ xx/ xxxx) SUMMARY: Your child has congenital adrenal hyperplasia (CAH) resulting from 3-beta-hydroxysteroid dehydrogenase deficiency. The adrenal glands do not make adequate amounts of cortisol, aldosterone, or androstenedione. Cortisol deficiency leads to compensatory ACTH release from the brain and the accumulation of adrenal androgens, especially DHEA. Chronic complications of CAH include electrolyte imbalances (hyponatremia, hyperkalemia, acidosis), growth disturbances, and abnormal sexual development. Acute adrenal insufficiency is life-threatening, and can cause hypoglycemia, seizures, or cardiovascular shock during an infection, surgery, or trauma. To prevent adrenal crisis during a period of significant illness, glucocorticoid ( steroid ) is given at 4-times the normal daily dose as hydrocortisone, mg/ m2 per day divided into four equal doses every 6 hours. For emergency situations during which seconds count, or if stress-dosing cannot be given by mouth (e.g. if child is vomiting, seizing, or unresponsive), inject SOLUCORTEF into muscle and call 911. HOME STRESS-DOSE THERAPY When Should I Start Stress-Dose Steroid Treatment at HOME? o Any significant illness associated with vomiting, diarrhea, poor formula/ food intake, labored breathing (e.g. pneumonia, asthma), or high fever (for example >101.5 F), or any elective or non-elective surgical procedure. o Stress dosing is typically NOT necessary for mild cold-like symptoms like runny nose, sneezing, mild cough, or low-grade temperature (>101.5F) and is NOT necessary for routine dental work (e.g. cavity filling) o Always notify a physician at the Clinic for Special Children ( ) when initiating stress dosing. Clinic doctors will guide you through proper duration of stress therapy and counsel you regarding when additional treatment measures are indicated. What Steroid Dose Should I Give? o If child is able to tolerate medication by mouth: HYDROCORTISONE tablet or liquid: 100 mg/ m 2 /day divided every 6 hours. o If child is vomiting, seizing, or unresponsive: SOLUCORTEF MUSCULAR INJECTION: mg/ m 2 /dose. Give Sugar, Salt, and Liquid o Given ample sugar and salt-containing liquids during illnesses. o Power Drinks like Gatorade are a good source of both sugar (carbohydrate) and salt. o For the lethargic child, emergency sugar sources include corn syrup, pancake syrup, liquid cake icing, and fruit juice. o Sugar and liquid intake should be frequent during illnesses; offer a liquid sugar source every 1-3 hours based on discussion with your CSC doctor. WHEN TO GO TO THE HOSPITAL: Persistent vomiting, high fever, difficulty breathing, unable to tolerate oral medication. WHEN TO CALL 911: Unresponsive, comatose, seizure. HOSPITAL TREATMENT OF ADRENAL CRISIS Circulation. Monitor heart rate, blood pressure, systemic perfusion, and cardiac rhythm. o Fluid resuscitation: ml/ kg boluses of normal saline (or dextrose 5% in normal saline) to stabilize circulation Hypoglycemia. Determine serum glucose STAT. o For hypoglycemia: dextrose mg/ kg/ dose (e.g. 2-4 ml/ kg of dextrose 10% solution) o Dextrose 5% or 10% in normal saline; continuous infusion at 1- to 2-times maintenance (e.g mg/ kg/ min). Hyperkalemia. Determine serum potassium and cardiac rhythm STAT. o Continuous glucose (8-12 mg/ kg/ min) and insulin ( Units/ kg-hr) infusion. o Calcium infusion. o Monitor serum glucose, serum potassium, and cardiac rhythm. o Cardioversion if necessary. Stress-Dose Glucocorticoid. Obtain: ACTH, 17-OH-pregnenalone, DHEA, electrolytes, glucose, beta-oh-butyrate, renin activity. o Acutely: Hydrocortisone IV/ IM: infant (0-3 y) 25 mg, child (3-12 y) 50 mg, adult (>12 y) 100 mg. o Then: Stress-dose hydrocortisone 100 mg/ m 2 / day divided every 6 hours. 1

2 Supplemental Table 1: Overview for Management of Salt-losing HSD3B2 Deficiency CASE STUDIES Four cases below, ordered by chronological age, represent the most serious complications of HSD3B2 deficiency. Case 1: Perinatal Adrenal Crisis LM was born in a community hospital at 37 weeks gestational age to a gravida 1, para 1 mother following an uncomplicated pregnancy. Labor was complicated by prolonged rupture of membranes, intrapartum fever, and chorioamnionitis. LM emerged vigorous with Apgars of 8 (1 min) and 9 (5 min), 2

3 but at 4 hours of life developed labored respirations and precipitous hypotension (Figure S1). She remained hypotensive for 30-hours, during which she developed anuria, hyponatremia (122 mmol/l), hyperkalemia (8 mmol/l), acidemia (total CO 2 16 mmol/l), and a run of unstable wide-complex ventricular tachycardia ablated with cardioversion. Insulin infusion for treatment of hyperkalemia was associated with iatrogenic hypoglycemia. Hydrocortisone (45 mg/m 2 ) was administered at 34 hours of life and hemodynamic and metabolic stability were achieved at 38 hours of life. The catastrophic postnatal interval was followed by severe epileptic encephalopathy, decerebrate posturing, and protracted irritability. Magnetic resonance imaging (day of life 6) revealed profound cytotoxic brain edema (Figure S1 D) and electroencephalogram showed dysynchronous background, voltage attenuations, epileptiform discharges, and absent state differentiation. LM s state newborn screening laboratory filter paper blood spot 17-hydroxyprogesterone level was within the reference range (16.4 ng/ml, cutoff for abnormal result > 19 ng/ml) but her adrenal glands were massively enlarged (length of right and left adrenals 4.2 and 5.3 cm, respectively; upper limit of normal for gestational age 1.3 cm), and genetic testing confirmed homozygosity for HSD3B2 c.35g>a on day of life 10. Other population-specific causes of neonatal encephalopathy (i.e. GLC, BRAT1, TSPYL) were excluded by molecular testing. At her present age of 6 months, LM has stagnant head growth (occiptofrontal head circumference Z score -6.5)(Figure S1 B), severe psychomotor delay, epilepsy, and evolving spastic quadriplegia. Since her perinatal event, she has required very large glucocorticoid doses (dexamethasone mg/m 2 /day) to control persistent elevations of ACTH and DHEA (Figure S1 C). Case 2: Hypoglycemic Seizure Following an Overnight Fast; Age 16 months KL had poor linear growth between birth and 6 months of age, prompting staged decrease of her morning dexamethasone dose (Figure S2 A). When she was seen as an outpatient at 8.5 months of age, growth velocity had improved and she was thriving. However, this was followed by a 7.5-month lapse in follow up during which she had no biochemical monitoring (Figure S2 D). At age 16 months KL was found in bed at 0630 h unresponsive and seizing 23 hours after receiving her last glucocorticoid dose. 3

4 Finger-stick glucose was undetectable (<20 mg/dl). Paramedics gave intramuscular glucagon as KL continued to seize en route to the hospital, where she arrived at 0830 h normotensive (systolic blood pressure 110 mm Hg, heart rate 100 bpm) with undetectable serum glucose. She was given intramuscular solumedrol and intravenous dextrose; three minutes later, blood glucose was 189 mg/dl and seizures abated. KL aroused with a Todd s hemiparalysis, but following 24 hours of intravenous glucose (6-12 mg/kg/min) and hydrocortisone (100 mg/m 2 /day) she was alert, active, and neurologically normal. Her beta-hydroxybutyrate level decreased from 2.6 to 0.7 mmol/l and cortisol (from exogenous dosing) was 10 µg/dl. KL was subsequently switched to nocturnal dexamethasone therapy and had stable linear growth along the 10 th centile on a dose of 0.17 to 0.23 mg/m 2 /day (Figure S2 A-D). Bone age was 4.2 years at chronological age 4.2 years. She suffered no permanent neurological sequelae. Case 3: Precocious Puberty, Advanced Skeletal Maturation, and Testicular Adrenal Rests; Age 11.5 years. By chronological age 10.5 years of age, while taking hydrocortisone equivalent doses of 17.2 ± 5.2 (range ) mg/m 2 /day, SI had a skeletal age of 13 years (Z score +3.0) and by 11.5 years, he had bilateral gynecomastia (palpable disc diameters 2.5 cm), Tanner IV pubic hair, and enlarged, firm, nodular testes (long axes of right and left testis 4.3 cm and 4.5 cm, respectively). Testicular adrenal rest tumors (TARTs) were detected by ultrasound (Figure S3 C). During this interval, ACTH levels ranged from 436 to 4436 pg/ml (reference 9-57 pg/ml) and DHEA levels were ng/dl (744 ± 617 ng/dl), up to 5-fold higher than age-adjusted reference values ( ng/dl). There was evidence of extraadrenal/extragonadal HSD3B1-mediated conversion of DHEA into more potent sex steroids, including androstenedione (67 ng/dl; reference ng/dl), total testosterone (207 ng/dl; reference ng/dl), and estradiol (23 pg/ml; reference 54 pg/ml). 17-hydroxyprogestone (70 ng/dl; reference ) and 11-deoxycortisol (27 ng/dl; reference 245 ng/dl) were also detectable in serum. ACTH and DHEA finally suppressed after several weeks of large 4

5 nocturnal dexamethasone doses (0.45 to 0.80 mg/m 2 /day), which entrained weight gain, moon facies, and arrest of skeletal maturation. Case 4. Sex Steroid Excess, Precocious Puberty, and Iatrogenic Complications of Suppressive Glucocorticoid Dosing. FM was diagnosed with HSD3B2 deficiency as an asymptomatic newborn. Between birth and 2 years of life, she grew normally on hydrocortisone replacement doses of mg/m2/day (mean 12.4 ± 7.2 mg/m 2 /day) divided thrice daily. Beginning at age 2.5 years, body mass index and linear growth rate markedly increased and she developed secondary sexual characteristics (Figure S2 E-H). Hydrocortisone dose was increased accordingly to 22 mg/m 2 /day, but was not sufficient to suppress persistent elevations of DHEA-sulfate ranging from 191 to 1263 µg/dl (mean 604 ± 364 µg/dl; normal reference range <100 µg/dl). By age 6, FM had pubic hair and tender breast buds (Tanner stage 3). A gonadorelin stimulation test indicated a peripheral cause of precocious puberty. She was treated with leuprolide acetate to suppress further pubertal development, but glucocorticoid doses required to suppress the HPA axis resulted in iatrogenic Cushing syndrome. At her current age of 18.5 years, FM suffers from polycystic ovary syndrome, hypertension, and morbid obesity (BMI 43.8 kg/m 2 ). 5

6 Supplemental Figure 1. (A) Four hours after a delivery complicated by chorioamnionitis, the child represented in Case 1 (LM) developed precipitous hypotension and hyponatremic, hyperkalemic acidosis that culminated in an unstable ventricular arrhythmia requiring cardioversion. Treatment of hyperkalemia with insulin infusion was associated with hypoglycemia. Intravenous hydrocortisone was administered at 34 hours of life (red arrow). (B) The child suffered severe ischemic-hypoglycemic brain injury, demonstrated by stagnant head growth during the first 6 months of life. (C) Protracted encephalopathy was accompanied by unrelenting pituitary ACTH hypersecretion and high adrenal DHEA output that could only be suppressed with hydrocortisone doses of mg/m 2 /day. Gray shaded vertical and horizontal areas in panel C represent, respectively, standard hydrocortisone replacement doses for infants with congenital adrenal hyperplasia and age-appropriate range for DHEA. (D) Axial fluid-attenuated inversion recovery (FLAIR) and diffusion imaging on day of life 6 show hyperintense swelling of frontal cortex and striata (yellow arrows), cavitating lesions in the subcortical white matter (yellow asterisks), and cytotoxic edema throughout the cortical gray matter (Ctx), striata (St), thalami (Th), midbrain (Mb), visual cortex (Vc), and cerebellum (Cblm). 6

7 Supplemental Figure 2. (A) KL (Case 2) had staged decrease of her morning dexamethasone dose between birth and 6 months of age due to poor linear growth (B) and rapid weight gain (C). This was followed by a 7.5-month lapse in follow up during which she had no biochemical monitoring (D), until age 16 months (red dotted line), when she was found seizing in bed 23 hours after receiving her last glucocorticoid dose. (E) FM (Case 4) was diagnosed with HSD3B2 deficiency as an asymptomatic newborn and grew normally between birth and 2 years on thrice daily hydrocortisone ( mg/m2/day). Beginning at age 2.5 years, linear growth (F) and body mass index (G) markedly increased and she developed secondary sexual characteristics. (H) Hydrocortisone dose was increased to 22 mg/m 2 /day, but was not sufficient to suppress DHEA-sulfate levels ranging from 191 to 1263 µg/dl (normal reference range <100 µg/dl). A gonadorelin stimulation test at age 6 (red dotted line) indicated a peripheral cause of precocious puberty. 7

8 Supplemental Figure 3. (A,B) Between 10.5 and 12.2 years, SI (Case 3) had persistent elevations of ACTH and DHEA (gray shaded areas represent age-appropriate reference ranges) on hydrocortisone doses of 17.2 ± 5.2 mg/m 2 /day. At age 10.5 years, skeletal age was advanced to 13 years (Z score +3.0). He developed bilateral gynecomastia, Tanner IV pubic hair, and enlarged, firm, nodular testes. (C) Bilateral testicular adrenal rest tumors (yellow asterisks) were detected by ultrasound. ACTH and DHEA suppressed after weeks of large dexamethasone doses (0.45 to 0.80 mg/m 2 /day), which entrained weight gain, moon facies, and arrest of skeletal maturation. 8