Adrenal Insufficiency and CAH - PowerPoint Presentation

1. Adrenal Insufficiency and CAHIsraa Ismail, MD

2. Objectives Review adrenal embryologyReview adrenal physiology and anatomyReview causes of primary adrenal insufficiency, including CAHReview causes of isolated hypoaldosteronism and pseudohypoaldosteronismPlan appropriate work up and management of primary adrenal disorders

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4. Embryology

5. Embryology

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9. Aldosterone regulation and effects

10. Image source: https://www.nature.com/articles/ncpendmet0481Credit Dr. DaytonSteroidogenesis pathway

11. Adrenal Cortex DisordersHypercortisolism (Cushing syndrome)Adrenal insufficiency (Addison disease)HyperaldosteronismHypoaldosteronismAndrogen excess Androgen deficiency

12. Adrenal insufficiency (AI)Difficult to diagnose in early lifeNon-specific features, dx is often missedNormal serum cortisol level is far lower compared to children and adults (especially in preterm)Malaise, fatigue & weaknessAnorexia or poor feedingNausea, vomiting (no diarrhea)Dehydration, hypotension not responding to pressorsHypoglycemia, hyponatremia, hyperkalemia, acidosisPoor growth

13. Adrenal insufficiency (AI)AI can be broadly divided into:Primary (hyperpigmentation, salt craving) vs secondary check ACTHCongenital vs acquired

14. Adrenal insufficiency (AI)/ Diagnosis

15. Adrenal insufficiency (AI)/ DiagnosisWhat do you do if a baby has persistent hypotension? What do you do if a baby received antenatal steroids and is now presenting with clinical picture of AI? What do you do with preterm baby, acutely sick, with low cortisol?

16. Adrenal insufficiency (AI)/ TreatmentThe physiologic secretion of cortisol is 6 mg/m2/d.Replacement dose 8-12 mg/m2/day of HCHigher doses initially in CAH and cholestasisIn adrenal crisis HC dose of 50-100 mg/m2 Avoid long-acting synthetic steroids, especially dexamethasone (Why?)Dose adjusted by clinical follow-up, growth rate, weight gain, BP and electrolytesIn primary AI, replace mineralocorticoid with fludrocortisoneDose 0.05-0.1mg, daily or BIDHigher doses in neonates (Why?) & cases of aldosterone resistanceAdjust according to electrolytes and BPIn infants add NaCl

17. Adrenal crisisLife threateningInadequate cortisol (+/- aldo)Triggered by stressors: illness, surgery, trauma, abrupt cessation of steroidsSevere hypotension, electrolyte abnormalities, acidosis, hypoglycemia, vomiting, seizure and even LOCTreat quickly and aggressively if suspected (draw cortisol level before if able)Stress dose steroids, fluid (without K), dextroseTreat hyperkalemia if EKG changes

18. Primary adrenal insufficiencyAutoimmune Adrenal Hemorrhage Infection- TB, fungi, HIV, CMVInfiltrative - Amyloidosis, HemochromatosisMalignant- Metastasis, LymphomaAdrenoleukodystrophyDrugs: Ketoconazole, etomidate, metyrapone, megaceCongenital adrenal hypoplasiaCongenital adrenal hyperplasiaMetabolic disorders: Smith-Lemli-Optz, Wolman diseaseMitochondrial disordersTriple A syndromeGlucocorticoid resistanceFamilial glucocorticoid deficiency types 1 & 2

19. Congenital Adrenal HyperplasiaGroup of inborn errors of steroidogenesis involved in production of cortisol, aldo or both1 in 13,000-16,000, varies by population90% - 21-hydroxylase deficiency 1 in 400 births in Alaskan Yupik Eskimos5-8% - 11-beta-hydroxylase deficiencyMost common form in Moroccan or Iranian Jewish descent<1% - 3-Beta-hydroxysteroid dehydrogenaseAutosomal recessive disorder, both sexes affected equally

20. Clinical manifestation of CAHDepends on severity of cortisol or aldo deficiency and on properties of the precursors or byproducts in excessCAH with salt wasting (loss of both cortisol & aldo):21-hydroxylase deficiency3-Beta-hydroxysteroid dehydrogenaseLipoid CAHDecreased cortisol but no salt wasting: 11-beta-hydroxylase deficiency17-alpha-hydroxylase deficiency

21. CAH/21 OH deficiency50-75% with salt wasting100% excess androgen100% cortisol deficiencyTested for on the Florida Newborn Screen17-Hydroxyprogesterone

22. CAH/21 OH deficiencyClassic: salt wasting (50-75%) vs simple virilizing (normal electrolytes)Clinical Presentation in FemalesAmbiguous genitaliaClinical Presentation in MalesIf severe, may present at 1-4 weeks with failure to thrive, vomiting, dehydration, hypotension, hyponatremia, hyperkalemia, hypoglycemia, or shock Non-classical (Late onset)Present in childhood or adolescence with sx of androgen excessNormal NBSNo salt wasting

23. Abnormal Newborn ScreenReference range based on GA and weightFalse positive results are common in sick and premature babies, or if NBS obtained before 24-48 HOLsFalse negative results if mother received antenatal steroids repeat in 1-2 weeks

24. Anormal NBS, what to do?Evaluate immediately:Weight lossDifficulty feedingVomitingHyperpigmentation (nipples or scrotum)Description of genitaliaFamily history of disorderAny other concerns provider or parent hasRepeat serum 17 OHP Obtain: serum electrolytes, plasma renin activity, ACTH

25. CAH/21 OH deficiencyDiagnosisGenetic testingCosyntropin (ACTH) Stimulation Test (250 mcg)At 0 & 60 min: Measure 17-OHP, cortisol, DOC, 11-deoxycortisol, 17-OH-pregnenolone, DHEA, and androstenedionePrecursor to product ratios are particularly useful in distinguishing the different enzymatic defectsTreatment:Glucocorticoid replacement (remember to stress dose)Mineralocorticoid replacementSalt supplement in infantsSurgery for female external genitaliaALL patients should have Solu-Cortef emergency kit at home for injection (life saving treatment)

26. 11-Beta-Hydroxylase Deficiency Androgen + mineralocorticoid excessFemales present with ambiguous genitaliaMales present later with precocious puberty and advanced skeletal maturationBoth will have hypertension (2/3) &/or hypokalemia (early childhood)A few may present with salt wasting crisis in infancy17 OHP can be moderately elevatedTreat with glucocorticoid, may use Spironolactone

27. 3-Beta-Hydroxysteroid Dehydrogenase DeficiencyLow cortisol, aldo, androstenedione but ↑DHEAClassic form with salt wasting in both M & FMales with incomplete virilizationFemales are virilizedNon classic forms present later as PCOSElevated 17 OH pregnenolone to 17OH progesterone ratio

28. 17-Hydroxylase DeficiencyFemales with normal genitalia, later HTN and delayed or absent pubertyMales with phenotypic female to ambiguous male genitalia, later HTN Dx may be suspected in an apparent female infant or young child with hx of an abdominal hernia, inguinal mass, or otherwise unexplained hypertension

29. Another cause of primary adrenal insufficiency picked up on NBS?

30. Adrenoleukodystrophy: X-linkedDefective oxidation of VLCFAs (peroxisomes)Accumulation of VLCFAs in brain, adrenal, liver, testesAI may present before or after neurologic symptomsX-linked ALD:Gene ABCD1 Xq28Present in childhood or adolescenceAddison only ALD (no neuro sx, 10%)On NBS in Florida (since 2018)Diagnosis:↑↑↑ VLCFA ABCD1 gene testingTreatment: Glucocorticoid & mineralocorticoid replacementStem cell transplant, Lorenzo’s oil (↓ VLCFA levels)

31. Adrenoleukodystrophy: Neonatal Autosomal RecessiveNeonatal (AR) ALD Variant of intermediate severity of the PBD-Zellweger syndrome spectrumPathophysiology: PEX mutationDefect in peroxisome assembly & functionPresence of C26:1 VLCFA↑ bile acids, ↓ plasmalogen, ↑ pipecolic acidPresentation of newbornCraniofacial abnormalitiesHypotoniaProgressive visual and hearing lossLeopard spot retinal pigmentationReplace glucocorticoids and mineralocorticoidsDeath <7 yrs oldSeizuresLiver diseaseAdrenal atrophy

32. Case 14-week-old presented to ED with vomiting, poor feeding, FTT Exam: no significant findingsWork up: hyponatremia, hyperkalemia, undetectable aldosterone level, high renin level, normal cortisol, high ACTH, and normal 17OHP. Abdominal US: no visualized right adrenalWas started on florinef and salt supplement with improved status and electrolytesHigh dose ACTH test: peak cortisol of 11.5DSD panel revealed the dx: NR0B1 mutation ?x-linked Congenital Adrenal Hypoplasia(Adrenal hypoplasia congenita)

33. Congenital Adrenal HypoplasiaNR0B1 (DAX-1): x-linked recessiveAdrenal crisis with salt wasting and hypoglycemia in infancyHypogonadotropic hypogonadism in adolescenceSF-1 (NR5A1): AR/ADHomozygous – 46 XY complete gonadal dysgenesis and AI in infancyHeterozygous- 46 XY some degree of GD and normal adrenal function in infancyhypogonadotropic hypogonadism in adolescenceAHC may be associated with IMAGe syndrome Intrauterine growth retardation, metaphyseal dysplasia, AHC and genital anomalies in malesCDKN1C mutation

34. Case 2 3-month-old male infant referred for evaluation of abdominal distension, diarrhea & failure to thrive. On exam: hepatosplenomegaly. Work up: High cholesterol and triglyceride, pancytopenia and abnormal liver function.Bone marrow aspirate: vacuolated macrophages.Imaging obtained ?Wolman disease (Lysosomal acid lipase deficiency)Shenoy P, Karegowda L, Sripathi S, et alWolman disease in an infantCase Reports 2014

35. Case 32 wk old male, GA of 30 wks, transferred to our NICU for concern for craniosynostosis. We were consulted for ambiguous genitalia.Exam: bifid scrotum with hypospadias, 2-3 toe syndactyly, and abnormal head shapeWork up: 46XY, with appropriate gonadotropins and T. 17 OHP, inhibin B and DHT were normal.  ACTH was slightly elevated. Had hyponatremia initially. High dose ACTH stim testing ruled out adrenal insufficiency (peak cortisol of 29.3 mcg/dl ). No internal uterus or ovaries on imaging. DSD panel: pathogenic variants in DHCR7 ?Smith-Lemli-Opitz Syndrome7-dehydrocholesterol was then checked and was high, biochemically confirmed SLOS. He was started on oral cholesterol supplementation

36. Case 4 Full term, macrosomic baby, traumatic vaginal delivery, APGARs 8 & 9. Admitted to NICU at 3rd HOL due to hypotonia, drowsiness, poor sucking with the impression of neonatal asphyxia and sepsis1st day worsening indirect hyperbili Low BP and dropping Hbg, concern for hypovolemic shock2nd day: scrotal swelling, hypoglycemia, hyponatremia and acidosisCoagulation studies were normalScrotal US: no testicular torsionAbdominal US and CT revealed the dx. ?Adrenal hemorrhageCortisol was checked and was 0.4 ng/dlTreated with blood transfusion and stress dose steroids

37. Case 5 6 yr old F: dark pigmentation of lips, elbows and knuckles, worsening vomiting, generalized weaknessHx of alacrimia since infancy, GERDa.m cortisol was 1.9 ng/dlBa swallow: dilated esophagusAperistalsis on esophageal manometry: achalasia ?Triple A Syndrome (Allgrove)AAAS mutation  aladinShah et al, AAA Syndrome, Case Report of a Rare Disease. Pak J Med Sci. 2017

38. Case 64 wk old male referred to liver unit for persistent cholestasis despite ursodeoxycholic acid tx since 4th DOLTerm birth, C section, AGAHypoglycemia requiring IV dextrose in the 1st DOL, TTN requiring O2 for 48 hrsExtensive eval was negative for liver or metabolic pathologyHormonal eval revealed: undetectable cortisol, very high ACTH (primary AI)Adrenal eval: Adrenal precursors were low. Nl testosterone (minipuberty). Renin and electrolytes were normal Exome analysis: homozygous for pathogenic variant in MC2R geneFamilial Glucocorticoid Deficiency (FGD)Di Dato et al, Case Report: Neonatal Cholestasis as Early Manifestation of Primary Adrenal Insufficiency. Front. Pediatr

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40. Hypoaldosteronism Isolated deficiency of CYP11B2 Hypotension, dehydration, hyperkalemia, hyponatremia, FTTHigh renin, low aldosterone, ↑ DOCMore severe in infancy seizure, coma and deathTx with Florinef and salt supplement

41. Case 76-day-old girl presented with vomiting, lethargy, and severe dehydration. No virilization or hyperpigmentationLab: Na 124, K 10, HCO3 10, elevated aldosterone, PRA & cortisol. Nl 17OHP. Elevated sweat chlorideFound to have RLL pneumoniaDeveloped ventricular tachycardia requiring cardioversion due to hyperkalemiaNormal renal ultrasound.Genetic testing: mutation in SCNN1A gene ?Pseudohypoaldosteronism Type I

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43. Case 88 months old M presented with vomiting, failure to thrive, HTN and medullary nephrocalcinosis.Labs: hypokalemia, metabolic alkalosis, hypercalciuria?Also hyporeninemic hypoaldosteronism & normal DOCDx suspected and confirmed the finding abnormally high ratio of urine cortisol to cortisoneTx with spironolactone resulted in growth, weight gain and blood pressure control. ?Genetics: homozygous mutation in HSD11B2 gene confirming the diagnosis of apparent mineralocorticoid excess (AME) Syndrome

44. Lu YT et al. Apparent mineralocorticoid excess: comprehensive overview of molecular genetics. J Transl Med. 2022

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