Primary Adrenal Insufficiency In Children

Mohamed Ahmed Abdullah University Of Khartoum Sudan Sudan and UAE Friendship Overview

• Basics

• Clinical Presentation

• Diagnosis

• Etiology

• Management The Adrenal Glands Circadian regulation Stressors (hypoglycemia, hypotension, Hypothalamus surgery, fever, injury) CRH

Vasopressin

Pro-inflammatory cytokines

ACTH

Adrenals

Cortisol ↑ K ↑ BP

A II + A III

A II ALDO

ACE A I Lung

↑ Renin ↑Na ↓K Renin ↑Blood Liver substrate volume ↑Renal Blood flow ↓Na+ ↑K+

CLINICAL FEATURES OF ADRENAL INSUFFICIENCY

•Chronic •Acute •Acute on chronic •+ signs and symptoms of aetiology (extradrenal) •GC/MC/Sex hormones/High ACTH Symptoms of GC Insufficiency

• Fatigue • Vomiting • Nausea and abdominal pain/diarrhoea • Symptoms of hypoglycemia • Weakness • Headache • Weight loss/FTT • Muscle aches and pains • Febrile episodes Symptoms and Signs Related to Sex hormones •DSD

•Hirsutism

•Acne Symptoms and signs of MC Deficiency •Dehydration •Collapse •Hypotension •Tachycardia •Dizziness •Wt loss and salt craving Hyperpigmentation Hyperpigmentation Malnutrition& Hyperpigmentation

CAUSES OF SKIN HYPERPIGMENTATION • Coeliac • ADDISONS • Kwashiorkor • B12&folate deficiency • Normal(or high) • Kalazar(leishmaniasi cortisol and ACTH in s) FGR • HIV • Methylmalonic aciduria with homocystinuria LABORATORY FINDINGS

• Hypoglycemia • Hyponatremia(90%) • High urinary sodium • Hyperkalemia(50%) • Acidosis • Esinophilia/lymphocytosis • Anemia • Small heart on x-ray/low voltage ECG • Absence of electrolyte disturbance does not exclude the diagnosis LABORATORY FINDINGS(cont.)

•Low cortisol basal and or on ACTH stimulation •High ACTH •↑ Renin •↓ Aldosterone •Normal or ↓ ACTH(features of 2dry) •Aetiology work up Early Morning Cortisol and ACTH

• Early morning Cortisol Less than 138 nmol/l =highly likely • Level between 138-450nmol/l likely/need ACTH stimulation test/or coverage during stress • DHAEAS if more than80ug/dl(2240nmol/l then AI is very unlikely • High ACTH • Sample has to be collected in heparin or EDTA plastic tube and immediately put in ice • Normal levels rarely exceed 50ng/l mostly above 200ng/l Short ACTH stimulation test(con)

• Increase in adrenal • Level above 500- metabolites in CAH 550nmol/l(18-20micg/dl- • Increase in cortisol in adrenal or 8-1omicgm/dl above hyperplasia but not adrenal basal indicates normality tumors • OR 2-3 fold increase in serum or 7 fold increase in salivary • If basal ACTH low proceed for HPA assessment tests • Cortisol UNITS 1micgm/dl=27.5nmol/l • Cannulate 30 min before • ACTH DOSE ? sampling • Neonates 15ug/kg • Up to 2yrs 125 • More than 2 250 Low dose Synacthen test

• To help in diagnosis of • How to prepare central adrenal • 250ug in 10 ml of insufficiency/subtleAI NS=25/ml • Use 1 ugm ACTH iv • 0.2ml in • Sample at 0,,30 min 1ml=5ug/ml(store) at • Normal above 4c 500nmol/l(600=100%s • 0.2ml in 1ml=1ug/ml ensitivity) • 100-500 suspect • Below 100-138nmol/l definite Urine or Serum Steroid Profile

• Urine GC/MS CAH

• Serum LC/MSMS circulating steroid hormones Age &Serum Cortisol levels

Age Value micrograms/dl Value nmol/l( x27.6)

26-28 weeks 1-11(6) 31-35 2.5-9.1(6.4) Full term 3days 1.7-14(6.2) 7 2-11(4.4) 31days-11month 2.8-23(9.4) Children 1-15yrs 8 AM 3-21(9.8)

Adults 8 AM 8-19(11) PM20-24 less than 50% of am Low sodium and High K

• Hypoaldosteronism • Normal cortisol, Normal ACTH, and and low aldosterone

• Pseudohypoaldosteronism • Normal cortisol and ACTH and high aldosterone • T1 a • T1b • T3 Differentiation of Primary from Secondary Adrenal Insufficiency Feature Primary Secondary or Tertiary Mineralocorticoid + - /rare deficiency Hyperpigmentation + - ICP - -/+ Other hormones + + deficiency signs Diabetes insipidus - -/+ Hoptension,shock,dehyd ++ +/- ration Hypoglycemia + ++ ACTH high low Aetiology of PAI Autoimmune SF1 ALD DAX-1 Infectious FIGURE 1 : ACTHR Etiologies of Addison’s Hemorrhagic/su disease. DAX-1, dosage- Adrenal rgery sensitive sex Insufficiency reversal- Metastatic adrenal hypoplasia Amyloidosis gene 1; ACTHR, Impaired steroidogenesis ACTH receptor (melanocortin-2 receptor) gene. Cholesterol Steroid biosynthesis biosynthesis CAH Smith-Lemli-Opitz Syndrome StAR Mitochondrial DNA Abetalipoproteinemia protein deletion

SF-1 steroidogenic factor 1, DAX-1 dosage-sensitive sex reversal – adrenal hypoplasia gene 1, ACTHR – ACTH receptor (melanocortin-2 receptor) gene, ALD – adrenoleukodystrophy, StAR – steroidogenic acute regulatory protein, CAH – congenital adrenal hyperplasia. Older than 14 yrs. From 2 - 14 yrs. Autoimmune Autoimmune adrenalitis From birth – 2 yrs. adrenalitis APS-2 peak age CAH APS-1 30 yrs AHC APS-2 APS-1 uncommon Contiguous gene ALD deletion syndrome AHC Rare : Rare : Rare : ALD A/R neonatal ALD Contiguous gene deletion AHC Mitochondrial deletion syndrome ACTH Smith-Lemli-Opitz Mitochondrial deletion syndrome unresponsiveness Smith-Lemli-Opitz syndrome ACTH unresponsiveness ACTH unresponsiveness

FIGURE 2 : Causes of Addison’s disease adrenal metastasis, hemorrhage, in boys. A/R, drugs, infections, amyloidosis are more likely with increasing age Autosomal-recessive Older than 14 yrs. From 3 - 14 yrs. Autoimmune Autoimmune adrenalitis From birth – 2 yrs. adrenalitis APS-2 peak age CAH APS-1 midlife (sexual ambiguity) APS-2 APS-1 uncommon

Rare : Rare : Rare : ACTH A/R sporadic AHC Mitochondrial deletion unresponsiveness A/R neonatal ALD Smith-Lemli-Opitz syndrome ALD Mitochondrial deletion ACTH unresponsiveness Smith-Lemli-Opitz syndrome ALD ACTH unresponsiveness

FIGURE 2 : Causes of adrenal metastasis, hemorrhage, Addison’s disease in girls. drugs, infections, amyloidosis are more likely with increasing age Disorder Gene OMIM Associated clinical features

Adrenal dysgenesis

X-linked adrenal hypoplasia congenita NROBI (DAXI) 300200 Hypogonadotropic hypogonadism, in some cases gonadotropin-independent precocious puberty

Steroidogenic factor 1 deficeincy NR5A1 (SF1) 184757 46, XY DSD, gonadal insufficiency

IMAGe syndrome CDKN1C 300290 IUGR, bone disorders and anomalies, genital anomalies, hypercalcemia, dysmorphic facial features Pallister –Hall syndrome GLI3 165240 Hypothalamic hamartomas, mesoaxial and postaxial polydactyly, bifid epiglottis, imperforate anus, genitourinary anomalies Meckel syndrome MKS1 249000 Cystic renal disease, CNS malformation- occipital encephalocele, polydactyly, hepatic abnormalities Pena –Shokeir syndrome DOK7,RAPSN 208150 Arthrogryposis,facial anomalies, IUGR, camptodactyly, fetal akinesia, polyhdramnion, pulmonary hypoplasia, cardiac defects, intestinal malrotation

Pseudotrisomy 13 264480 Holoprosencephaly , polydactyly, craniofacial anomalies Hydrolethalus syndrome HYLS1 236680 Hydrocephaly , micrognathia, polydactyly,abnormal genitalia, congenital heart defects, respiratory organ defects

Galloway –Mowat syndrome 251300 Nephrotic syndrome, microcephaly, encephalopathy, diaphragmatic hernia Adrenal insufficiency DAX - 1 hypogonadism Hyperthelorism, alternating 22.1 strabismus, a drooping mouth, GKD pseudotriglyceridemia 21.1 elevated glycerol in the serum and urine Isolated form can present as hypoglycemic coma

DMD/BMD muscular dystrophy elevated C/K/aldolase CYBB Chronic granulomatous disease Del Xp2.1 – Xp22.11 Psychomotor I11RAPPL1 FIGURE 4 : contiguous gene retardation deletion syndrome. DAX-1, Dosage-sensitive sex Del Xp21.1 – Xp22.11 Agenesis of the corpus reversal-adrenal hypoplasia collusum gene 1; GKD, glycerol- kinase deficiency; Del Xp21.2 High frequency DMD/DMD, Duchenne / Becker muscular dystrophy; hearing loss II1RAPL-1, gene for Deletion Xp21.3 Ocular albinism interleukin 1 receptor family; - Xp21.2 OTCD, ornitine OTCD transcarbamoylase Elevated NH3, deficiency Retinitis pigmentosa oroticaciduria

Cholesterol Synthesis Disorders

Disease Gene Clinical

Wolman LIPA Lipid in various organs,adrenal calcification hepatosplenomegaly steatorrhoea Smith Lemli Opitz DHCR7 Multiple congenital maformations disease and mental retardation

Abetalipoproteinemia MTP Ataxia,retinopathy,acanthocytosis and mental reardation

Familial LDLR Xanthoma,corneal arcus,coronary hypercholesterlemia Smith- lemli- Optiz Syndrome

Disorder Gene OMIM Associated clinical features

Defects of steroid biosynthesis

Congenital lipoid adrenal hyperplasia StAR 201710 46,XY,DSD,gonadal insufficiency

P450 side chain cleavage syndrome CYP11A1 118485 46,XY,DSD,gonadal insufficiency

3β -hydroxysteroid dehydrogenase deficiency HSD3B2 201810 46,XY,DSD and 46,XX,DSD,gonadal (CAH) insufficiency

21 -hydroxylase deficiency (CAH) CYP21A2 201910 46,XX,DSD,androgen excess syndrome, testicular adrenal rest tumors 11β -hydroxylase deficiency (CAH) CYP11B1 202010 46,XX,DSD,hypertension, androgen excess syndrome 17-hydroxylase defeciency (CAH) CYP17A1 202110 46,XY,DSD,hypertension,gonadal insufficiency

P450 oxidoreducatse deficiency (CAH) POR 613571 46,XY,DSD and 46,XX,DSD,gonadal insufficiency ,Antley-Bixler skeletal malformationsyndrome,changes in drug metabolism

Aldosterone synthase deficeincy CYP11B2 124080 Isolated MC deficiency

Cortisone reducatse defeciency HSD11B1 614662 Androgen excess syndrome

Apparent cortisone reductase deficency H6PDH 604931 Androgen excess syndrome STAR DEFICIENCY Double hit theory CAH

 DSD  GCD  MCD  Hypo or hypertension

P450 Oxidoreductase Deficiency(POR) • Crucial electron donor to all microsomal P450 cytochrome(CYP) enzymes • Clinical • AI • XY &XX DSD • Delayed puberty • Skeletal malformation(Antley-Bixler craniosynostosis syndrome) • Steroid profile • Genetic testing POR gene Cortisone Reductase Deficiency(HSD11B1) • Inability to convert cortisone to Cortisol • Low urinary cortisol metabolites and high cortisone metabolites • High ACTH • Excess androgens,prematur e adrenarche and PCOS Diagnosis 8am sample(LC MS/MS) Genetic Testing

• StAR

• CYP11A1

• Others ACTH RESISTANCE disease Gene clinical

FGD MC2R Normal MC tall stature MRAP

DNA repair MCM4 NK cell deficiency,short stature defect ,microcephaly,recurrent viral infectios,chromosomal breakage

AAAA(Allgroe AAAS Alacrima,Achalasia,AI,Hyperkeratosis,low IQ syndrome

Deficiency of NNT, Only GC deficiency mitochondrial TXNRD2 Only GC deficiency radicals detoxification AAAA (Allgroves)Syndrome Allgroves Syndrome Familial Glucocorticoid Resistance

• AD AR Cortisol Cytokines G • Signs of 2NUCLEUS NFkB R G hyperandrogenism R • PCP

• Hypertension and Coa Coa 1 H G G ctiv _3 ctiv k alkalosis S + C-fosC-jun Rator B H R ator • No much symptoms of P Co S Com mpl PAI P plex ex • High cortisol and ACTH Inflamma 1 tory • Treat with response 1 k dexamethazone and + (TNF, thiazide diuretics IL-1β, Il- B 6, IL-8, 1 CELL MCSF) k MEM B BRAN E Disorder Gene OMIM Associated clinical features

Metabolic disorders peroxisomal defects

X-linked adrenoleukodystrophy ABCD1 300100 Progressive neurodegeneration ,dementia, progressive behavioral disturbances, vision and hearing loss, spasticity and seizures; accumulation of very long chain fatty acids

Neonatal adrenoleukodystrophy PEX1 601539 Hypotonia ,seizures, diffuse encephalopathy, sensorineural hearing loss, peripheral neuropathy, mild facial dysmorphism, autosomal recessive

Infantile Refsum disease PHYH,PEX7 266500 Anosmia, retinitis pigmentosa, neuropathy, deafness, ataxia, ichthyosis

Zellweger syndrome PEX1 and 214100 Severe neurologic dysfunction with other PEX handicaps, craniofacial abnormalities, genes severe mental retardation, hepatomegaly, growth failure, stippled epiphysis, genitourinary anomalies Disorder Gene OMIM Associated clinical features

Metabolic disorders: mitochondrial defects

Kearns –Sayre syndrome mitDNA del 530000 Progressive external ophthalmoplegia , pigmented retinopahty, cardiac conduction block, cerebellar ataxia; other endocrine pathologies Adrenal leukodystrophy Peroxisomal Disorders Disorder Gene OMIM Associated clinical features

Autoimmune disorders

Isolated autoimmune adrenalitis CTLA-4 ,HLA- DR3, HLA- DR4,HLA-B8

Autoimmune polyglandular AIRE 240300 Hypoparathyrodism , candidiasis, syndrome, type 1 autoimmune hypergonadotropic hypogonadism, autoimmune thyroid diseases , alopecia, chronic autoimmune hepatitis, pernicious anemia, vitiligo Autoimmune polyglandular CTLA-4 ,HLA- 269200 Autoimmune thyroid diseases , syndrome, type 2 DR3, HLA- TIDM, premature ovarian failure, DR4 pernicious anemia, celiac disease

Autoimmune polyglandular CTLA-4 ,HLA- Combination of autoimmune diseases syndrome, type 4 DR3, HLA- not included in previous groups DR4

APE Syndromes % 1 2(schmidts) hypoparathyroidism 80+ rare Addisons 60+ common hypogonadism 30+ 30 - thyroiditis 10- 70+ DM1 20- 40-50 hypopituitrism uncommon rare MCC 80-100 Not seen ED 75+ Not seen alopecia 25-30 Less than 10% Pernicious anemia 10-15 variable hepatitis 10-15 rare malabsorption 10-15 rare vitiligo 10 10 aspleism uncommon Not seen keratoconjuctivitis uncommon rare Disorder Associated clinical features

Acquired defects Hemorrhage In newborn infants or neonates after delivery , coagulopathy

Infections Septic shock, Waterhouse-Frederichsen syndrome- meningococcal disease, tuberculosis, fungi, HIV-1, CMV

Surgery , trauma Bilateral adrenalectomy, (McCune-Albright syndrome)

Infiltration Metastasis, lymphomas, amyloidosis, sarcoidosis, hemochromatosis

Drugs GC treatment withdrawal syndrome ;ketoconazole , rifampicin, phenytoin, phenobarbital, etc.

Neonatal Adrenal hemorrhage CLINICAL FEATURES OF ACUTE ADRENAL INSUFFICIENCY • Abdominal pain • Vomiting • Diarrhoea • Dehydration • Weakness.malaise.muscle pains • Hypothermia/hyperthermia • Hpoglycemia symptoms • hypotension • Shock • Coma • FEATURES OF AETIOLOGY ACUTE ADRENAL INSUFFICIENCY

• SUSPECT IN A PT WITH • Known hypoadrenalism • Chronic steroid therapy • Ambiguous genitalia • Toxemia&skin rash • Hyperpigmented skin • Features of syndromes or conditions associated with hypoadrenalism AAI LAB FINDINGS • Serum cortisol low • ACTH /high/low • Na low • K high • CHO3 low • Glucose low • Urea&creatinine • Eosinophilia • Investigation for aetiology • Absence of electrolyte disturbance does not exclude the diagnosis MANAGEMENT OF ADRENAL CRISIS

• ABC • IV hydrocortisone • 25,50,100 mg for infants,children,adolescents • Treat hyoglycemia • Treat hyponatremia • Treat hyperkalemia • Treat acidosis • Treat ppting factor • ICU monitoring LONG TERM MANAGEMENT • Hydrocortisone tab 10-15mg/M2/day BID/TID • Equivalent dose of prednisolone can be used BID • 20mg HC=5mg pred=0.8-1mg dexa • FLUDROCORTISONE 50-300UGM/day/plus oral salt • COVERAGE DURING STRESSX2-3TIMES • Hydrocortisone Injection at home • Alert card/Lace • Treat comorbidities and aetiology • FOLLOW UP Novel Hydrocortisone Formulations • Modified Release HC PO OD multiparticulate capsules • Decreased androgen level • Decreased hydrocortisone equivalent dose • Decreased 17OHP

• HC continuous SC infusion with insulin pump to mimic circadian rhythm (6 months trial) • Adequate ACTH suppression • Low total hydrocortisone dose • Improved fatigue and quality of life • No change in TART or insulin resistance • HC succinate preparations not designed for sc therapy/local reactions • Very low dose HC granules for treatment of infants on trial

The Nubian Kingdoms of Sudan 3500BC THANKS