QAP Case Presentation 16-05 Dr Lan Nguyen Chemical Pathology Registrar Pathology North- RNSH

Case 16-05 4 week old term baby boy Emergency department Clinical notes: Failure to thrive. Severe vomiting for 2-3 days Results on admission: Sodium 111 L mmol/L (133 - 144) Potassium 7.9 H mmol/L (4.2 - 6.7) Chloride 83 L mmol/L (97 - 110) Bicarbonate 17 mmol/L (16 - 29) Urea 10.4 H mmol/L (1.3 - 5.7) Creatinine 50 H umol/L (11 - 36) Note: Australasian Harmonised Reference Intervals for Paediatrics (AHRIP)

Question 1 Would you notify these results? Sodium 111 L mmol/L (133 - 144) Potassium 7.9 H mmol/L (4.2 - 6.7) Chloride 83 L mmol/L (97 - 110) Bicarbonate 17 mmol/L (16 - 29) Urea 10.4 H mmol/L (1.3 - 5.7) Creatinine 50 H umol/L (11 - 36) Would you notify these results? Severe hyperkalaemia and hyponatraemia needs to be acted on urgently.

Question 2 What is the most likely underlying cause of this presentation and results? A. Pyloric Stenosis B. Pseudohypoaldosteronism C. UTI &/or urinary tract malformation D. Congenital adrenal hyperplasia

Question 2 What is the most likely underlying cause of this presentation and EUC results? A. Pyloric Stenosis B. Pseudohypoaldosteronism C. UTI &/or urinary tract malformation D. Congenital adrenal hyperplasia Associated with low K, metabolic alkalosis

Hypoaldosteronism: Sodium wasting Volume depletion Potassium retention Type 4 RTA Hypoaldosteronism- deficiency of aldosterone. hypereninaemic : aldo synth defect, CAH, Addison’s Hyporenin- renal tubulointerstitial disease (analgesia/lead nephropathy), diabetic nephropathy, drugs (NSAIDs, ACEI, cyclosporin) (Williams Textbook of Endocrinology, 12e)

Pseudohypoaldosteronism (PHA) Liddle syndrome 2a. AR PHA1B 2b. AD PHA1A 3. Bartter syndrome 4. Gitelman syndrome 5. Gordon syndrome (PHA2) Type 1 resistance to aldosterone Type 1 Renal- AD defect Mineralocort receptor gene. Milder presentation Type 1 Systemic - AR ENaC channel genes (inactivating). Severe presentation (Type 2- WNK kinases defect (increase Na-Cl co-transporter, decrease K channel expression increased Na reabs  less Na delivery to CD and Enac abs less electroneg drive for K and H secretion).  HTN, hyperkal, met acidosis. (O’Shaughnessy & Karet, J Clin Invest, 2004)

Question 2 What is the most likely underlying cause of this presentation and EUC results? A. Pyloric Stenosis B. Pseudohypoaldosteronism C. UTI &/or urinary tract malformation D. Congenital adrenal hyperplasia Rare, prevalence <1 per million (Orphanet) Type 3, transient or secondary hypoaldost Secondary causes: Excessive salt loss (intestine, sweat-CF) Nephropathy eg. Obstruction, UTI, amyloidosis Mechanism- aldosterone resistance due to ?inhibitory effects of inflammatory cytokines Responds rapidly to fluid/electrolyte and antibiotic rx

Question 2 What is the most likely underlying cause of this presentation and EUC results? A. Pyloric Stenosis B. Pseudohypoaldosteronism C. UTI &/or urinary tract malformation D. Congenital adrenal hyperplasia Transient aldosterone resistance ? Clinical features/history Type 3, transient or secondary hypoaldost Secondary causes: Excessive salt loss (intestine, sweat-CF) Nephropathy eg. Obstruction, UTI, amyloidosis Mechanism- aldosterone resistance due to ?inhibitory effects of inflammatory cytokines Responds rapidly to fluid/electrolyte and antibiotic rx

Question 2 What is the most likely underlying cause of this presentation and EUC results? A. Pyloric Stenosis B. Pseudohypoaldosteronism C. UTI &/or urinary tract malformation D. Congenital adrenal hyperplasia Must exclude adrenal crisis due to CAH Incidence 1 in 15000 live births

Adrenal Steroidogenesis Han, T. S. et al. (2013) Treatment and health outcomes in adults with congenital adrenal hyperplasia Nat. Rev. Endocrinol. doi:10.1038/nrendo.2013.239

Question 3 This clinical presentation is likely to be due to a defect in which enzyme? A. 21-hydroxylase B. 3-beta-hydroxysteroid dehydrogenase C. 17- hydroxylase D. 11-hydroxylase

11-hydroxylase Deficiency 5-8% CAH May present with salt-wasting but usually presents with: HTN and hypoK (excess MC action of 11-DOC) Ambiguous genitalia/hyperandrogenism (Han TS et al, Nat Rev Endocrinol, 2013)

17- hydroxylase Deficiency Rare cause of CAH Presents with: HTN and hypoK (excess MC) Delayed puberty (Han TS et al, Nat Rev Endocrinol, 2013)

3-beta-hydroxysteroid dehydrogenase Deficiency Rare cause of CAH Peripheral conversion to androstenedione, testosterone Presents with: Salt-wasting, hyperkalaemia Virilisation (F) and ambiguous genitalia/delayed puberty (M) (Han TS et al, Nat Rev Endocrinol, 2013)

21-hydroxylase deficiency ~90% CAH (Han TS et al, Nat Rev Endocrinol, 2013)

21-Hydroxylase deficiency CAH Classical CAH Neonatal or early infancy presentation Salt-wasting form (67%) Hyponatraemia, hyperkalaemia Failure to thrive, vomiting, dehydration Simple-virilising form (33%) Ambiguous genitalia, virilisation Non-classical CAH Later onset presentation Androgen excess: premature puberty, hirsutism, infertility

Question 4 This baby boy was born in Victoria, Australia. Could the outcome have been different had the patient been: A. Female? B. Born in New Zealand? Likely Yes! Case from a baby cor

NZ CAH Screening Outcomes 1994-2013 1 175 973 newborns screened 44 CAH 23 Clinical Suspicion 22 Female 1 Male (FHx) 21 Positive Screening 6 Female 4 virilisation 15 Male 3 virilisation 3 vomiting 1st line: 17OHP Delfia immunoassay 2nd line: 17OHP>2SD  reassay after diethyl ether extraction If high request whole blood sample, same day pediatrician rv if very high FP rate high, PPV 1% (problem in stressed prem babies) ?Cost benefit if avoid salt-wasting crises, future morbidity Age at treatment (Mean, SD) 3.9 d, 2.2 12.0 d, 6.7 Cost NZ $69,489 per case PPV 1% No adrenal crises No missed cases

Question 5 Which further tests would you recommend? A. Blood glucose B. ACTH and cortisol C. 17-OH progesterone D. Renin and aldosterone E. Urine steroid profile

Question 5 Which further tests would you recommend? A. Blood glucose B. ACTH and cortisol C. 17-OH progesterone D. Renin and aldosterone E. Urine steroid profile

Management of Adrenal Crisis Fluid resuscitation Correct hypoglycaemia/electrolyte abnormalities Steroid replacement with IV hydrocortisone Ideally, collect samples prior to steroid replacement. Do not delay steroid replacement to collect samples or await further results.

Suggested Comment The clinical presentation and electrolyte results are suggestive of classic salt- losing congenital adrenal hyperplasia. Suggest urgent testing for blood glucose, cortisol, 17-OHP, ACTH, renin and aldosterone. However, this should not delay the urgent management including fluid, electrolyte and steroid replacement.