Polyglandular auto immune syndrome an endocrinology subject

1. POLYGLANDULAR AUTO
IMMUNE SYNDROME
By Dr. anmar Dhia aldeen
SCE endocrinology and diabetes

2. Patient is mariam sameer hassan 9 years old
height 125 cm wt 21 kg diagnosed with
hypoparathyroidisim at age 2 years and by Addison
disease at age 8 years have history of
 allopicia ariata
 hyperpigmentation
hypocalcimia associated fits

3. Autoimmune injury causes 15 percent of cases of primary
adrenal insufficiency in children Approximately one-half of
patients with autoimmune adrenal insufficiency also have
autoimmune destruction of other endocrine glands. more
frequently in females.

4. Causes of primary adrenal insufficiency in children
Steroidogenesis disorders
Congenital adrenal hyperplasia
21-hydroxylase deficiency (CYP21A2 mutations)
11-beta-hydroxylase deficiency (CYP11B1 mutations)
17-alpha-hydroxylase deficiency (CYP17A1 mutations)
3-beta-hydroxysteroid dehydrogenase deficiency (HSD3B2 mutations)
Congenital lipoid adrenal hyperplasia (StAR protein deficiency)
P450 side-chain cleavage deficiency (CYP11A1 mutations)
P450 oxidoreductase deficiency (apparent combined CYP21A2 and CYP17A1
deficiency)
Defects in aldosterone production
Aldosterone synthase deficiency (CYP11B2 mutations)
Defects in cholesterol biochemistry
Lysosomal acid lipase deficiency (Wolman disease)
Smith-Lemli-Opitz syndrome

5. Causes of primary adrenal insufficiency in children
Adrenal damage or dysfunction
Bilateral adrenal hemorrhage of the newborn
Adrenal hemorrhage of acute infection
Autoimmunity
Polyglandular autoimmune syndromes
Infection
Tuberculosis
Fungal infection
Human immunodeficiency virus
CMV
Mitochondrial diseases due to mitochondrial DNA mutations (eg, some cases of
Kearns-Sayre, Pearson, or MELAS syndromes)
CIRCI critical illness-related corticosteroid insufficiency
Transient adrenal insufficiency in premature infants

6. Causes of primary adrenal insufficiency in children
Drugs
Aminoglutethimide
High-dose ketoconazole
Mitotane
Etomidate
Peroxisomal defects
Adrenoleukodystrophy/adrenomyeloneuropathy (X-linked)
Zellweger syndrome and its variants (autosomal recessive)
Abnormal adrenal development
X-linked adrenal hypoplasia congenita due to NR0B1/DAX1 mutations
Adrenal hypoplasia due to NR5A1 (SF1) mutations
IMAGe syndrome
SGPL1 mutations
Inherited adrenal unresponsiveness to ACTH*
Familial glucocorticoid deficiency (MC2R or MRAP mutations)
Triple A syndrome (AAAS mutations)

7. Polyglandular autoimmune syndrome type 1
is a rare autosomal recessive disorder females > males
Genetics :mutations in the autoimmune regulator (AIRE) gene on chromosome 21q22.
it is important in the selection and generation of regulatory T cells
Hypoparathyroidism or chronic mucocutaneous candidiasis is the first manifestation,
appearing during childhood
Adrenal insufficiency usually develops later, at age 10 - 15 years.
antigen targets (17-alpha-hydroxylase), (21-hydroxylase)
Primary hypogonadism occurs in 60 percent of patients
Malabsorption and other gastrointestinal disorders occur in 25 percent of patients
autoantibodies to tryptophan hydroxylase, an intestinal antigen
17 percent had autoimmune chronic active hepatitis with antibodies directed against
aromatic l-amino acid decarboxylase
The variable clinical presentation and is due to environmental factors and genetic
factors other than AIRE gene

8. Polyglandular autoimmune syndrome type I
Endocrine
Endocrine Abnormality %
Hypoparathyroidism 89
Chronic mucocutaneous candidiasis 70
Adrenal insufficiency 60
Primary hypogonadism 45
Hypothyroidism 12
Type 1 diabetes mellitus 1
Hypopituitarism <1
Diabetes insipidus <1
Nonendocrine abnormality
Malabsorption syndromes 25
Alopecia totalis or areata 20
Pernicious anemia 16
Chronic active hepatitis 9
Vitiligo 4

9. Polyglandular autoimmune syndrome type 2 (Schmidt's syndrome)
much more prevalent than the type I
most cases between age 20 and 40 years
primary adrenal insufficiency is its principal manifestation
Antibodies to steroidogenic enzymes are present
Autoimmune thyroid disease and type 1 DM more common
Primary hypogonadism can occur
autoimmune hypophysitis, preferentially causing ACTH deficiency and also
GH difficiency
Hypoparathyroidism does not occur in this disorder
one-half of cases are familial and several modes of inheritance (autosomal
recessive, autosomal dominant, and polygenic)
Males >females

10. Polyglandular autoimmune syndrome type II
Endocrine abnormalities %
Adrenal insufficiency 100
Autoimmune thyroid disease 70
Type 1 diabetes mellitus 50
Primary hypogonadism 5 to 50
Diabetes insipidus <1
Nonendocrine
Vitiligo 4
Alopecia, pernicious anemia, myasthenia gravis, immune
thrombocytopenia purpura, Sjogren's syndrome, rheumatoid
arthritis ≤1

11. Clinical manifestations of adrenal insufficiency
glucocorticoid deficiency
Gastrointestinal symptoms (nausea, vomiting)
Fatigue, weakness
Failure to thrive
Morning headache
Fasting hypoglycemia
Increased insulin sensitivity
Decreased gastric acidity
Decreased free water clearance

12. Mineralocorticoid deficiency
Hypotension, dizziness
Muscle weakness
Fatigue
Gastrointestinal symptoms (nausea, vomiting, anorexia)
Salt craving
Weight loss
Dehydration
Hyponatremia, hyperkalemia, metabolic acidosis

13. Adrenal androgen deficiency in females
Decreased pubic and axillary hair development in
pubertal patients
Decreased libido in older patients
Increased melanocortin from POMC
cleavage products
Hyperpigmentation of skin, mucosa, palmar
creases, axillae, gingival borders

14. Dignosis of adrenal insufficency
Primary adrenal insufficiency is indicated by high
adrenocorticotropic hormone (ACTH) and low
cortisol concentrations that fail to rise with
stimulation by cosyntropin stimulation test
mineralocorticoid deficiency, low aldosterone,
elevated plasma renin activity (PRA),
hyponatremia and/or hyperkalemia

15. treatment hydrocortisone the first-line agint in pediatric cases .
short duration of action and lower potency , for fine titration to the optimal dose
Predensolone more growth suppression and need to increase fludrocortisone
oral dose of hydrocortisone is in the range of 7 to 10 mg/m2/day
Shorter half life of oral hydrocortisone and partially destructed by gastric acidity
The total daily dose is divided into three doses and administered every eight hours
usual daily dose of fludrocortisone is 0.1 mg when given with hydrocortisone
the mineralocorticoid dose is not adjusted by age or surface area, because the
aldosterone secretion rate is nearly constant throughout the lifespan
Adjustments in the doses of hydrocortisone and fludrocortisone are based primarily
upon rates of growth and on skeletal maturation (bone age). In addition, serial
measurements of electrolytes and plasma renin activity (PRA) should be performed to
monitor for mineralocorticoid sufficiency.
Fine adjustment is based on clinical judgment and electrolyte level

16. Treatmentof hypoparathyroidisim in children
Initial treatment Calcium and Vit D
25 to 50 mg/kg (up to 1000 to 2000 mg) elemental calcium daily (total diet +
supplement) in divided doses (calcium glubionate, calcium carbonate, or calcium
citrate)
Calcitriol short half life 4-6 hours, need no renal activation by parathormone,
rapid onset of action
Children >1 year:
◾Initial: 0.25 mcg once daily
◾Maintenance: •Children 1 to 5 years: 0.25 to 0.75 mcg daily
•Children ≥6 years: 0.5 to 2 mcg daily
Hydrochlorothiazide (if required to control hypercalciuria) 12.5 to 50 mg daily 0.5
to 1.5 mg/kg per day (maximum 50 mg daily)
Should not be used with Addison disease
maintain the serum calcium concentrations within the low-normal range and to
avoid hypercalciuria

17. Side effect of treatment hypercalciuria, which, if chronic, can cause nephrolithiasis,
nephrocalcinosis, and renal failure
Reduce the dose if urinary 24 hours calicium ecreation above 300mg /day
Add thiazide if urinary calicium >250 mg /24 hours
2nd line treatment
Recombinant human PTH — Subcutaneous administration of PTH 1-34 and PTH 1-84 is
effective in reducing the doses of oral calcium and vitamin D supplementation in
patients with hypoparathyroidism
also improve abnormal skeletal properties in hypoparathyroidism, in which bone
turnover may be quite reduced and improve (BMD) significantly
The goal is to find the lowest dose of PTH 1-84 to maintain the serum calcium
concentration in the lower half of the normal range,
,although data are not available in humans, PTH 1-84 is contraindicated in patients
who are at increased risk for developing osteosarcoma, such as patients with a prior
history of external beam radiation therapy or paget disease of bones also increase risk
in children

18. Thank you