Pediatric endocrinology, Case presentation, Rare case, Interesting case, CAH, Aldosterone synthase deficiency, RTA, failure to thrive, clinical meetin

1. Who moved my salt?
Dr. Arun George
Paediatric endocrinology

2. Case 1
• 7 months old girl, 1st born of 3° consanguineous parentage
• Poor weight gain since birth
• development delay predominantly motor
• feeding difficulty s/o GERD since birth
• ANC - normal, foetal movements appreciated well.
• PN – FT, LSCS for NRFS, cried at birth, BW 3kg
• Neonatal period- hyperbilirubinemia, phototherapy provided

3. O/E
• Active, alert, afebrile
• Weight: 4.6kgs (Exp -7.9 Kg) , 58% of expected ( Grade 3 PEM)
• Length: 60 cm
• Head circumference: 42 cm (Microcephaly)
• Sparse and lustreless hair, Large AF, skin pigmentation- normal
• Dysmorphism- prominent forehead, deep set eyes, pinched nose,
anteverted nares, low set small ears, thin upper lip (similar like mother )
• CNS : Moves all limbs well, hypotonia, DTRs brisk
• PA - Liver 2 cm below costal margin

4. Case 2
• 4 months old boy, 1st born of 3° consanguineous parentage
• Poor weight gain since birth
• Motor development delay
• Faulty feeding – Lactogen by bottle feeds
• ANC – Teenage pregnancy, mother weight gain- 8 Kg, USG – IUGR
• PN- 37+3w, NVD, Apgar 9&10, BW 2.2 Kg
• Neonatal period – Normal

5. O/E
• Active, alert, afebrile
• Weight: 2.4 Kgs (Expected -5 Kg), 48% of expected ( Grade 4 PEM)
• Length: 50cm (61.5 cm)
• Head circumference: 36.5 cm (40-42 cm)(Microcephaly);
• Prominent scalp veins, Left undescended testis
• Skin- normal
• CNS : Moves all limbs well, hypotonia, DTRs brisk
• Rest of systemic examination normal.

6. CASE 1
• Counts – Normal
• Thyroid functions –WNL
• Stool fat globules- No fat globules
seen
• Urine organic acids – positive
unidentified peak
• Serum amino acids- Normal
• Serum Biotinidase levels - 38.67
(29.46 ± 9.11)
• Serum carbohydrate deficient
glycoprotein - negative
• CASE 2
• Hb – 9 gm/dL, rest counts normal
• Thyroid functions –WNL
• Urine organic acids – normal
• Serum amino acids- Normal
• Carnitine levels – Normal
Investigations

7. Case 1 Case 2
• Sodium- 128 m mol/L
• Potassium- 5.7 m mol/L
• Bicarbonate- 15 m mol/L
• Urine spot Na- 44 (upto 20 mmol/l)
• Blood Lactate- 4.5 mmol/L
• Ammonia- 116 ug%
• Creatinine – 0.31 mg%
• Progesterone-17 Hyd - 0.3ng/ml
• Sodium- 123 m mol/L
• Potassium- 8 m mol/L
• Bicarbonate- 16 m mol/L
• Urine spot Na- 41 (upto 20 mmol/l)
• Blood Lactate- 4.2 mmol/L
• Ammonia- 62 ug%
• Creatinine – 0.24 mg%
• Progesterone-17 Hyd - 1.0ng/ml

8. • X ray - Bone age appropriate, no
dysostosis
• USG abdomen - Normal
• ECHO Normal
• USG abdomen – Left UDT in sup.
Inguinal region

9. Thus
• Both patients had post-natal growth failure with Motor delay
• Examination Grade 3-4 PEM, Hypotonic
• Hyponatremia, hyperkalemia
• Salt wasting on urine Spot Sodium

10. DIFFERENTIALS..???

11. Differentials:
Congenital adrenal
hyperplasia
Hypoaldosteronism
Pseudohypoaldosteronism

12. Causes of Hypoaldosteronism
1.Primary
-Primary adrenal
insufficiency
-Congenital adrenal
hyperplasia
-Isolated aldosterone
synthase deficiency
2. Hyporeninemic
Hypoaldosteronism
-Renal disease – diabetic
nephropathy
-Volume expansion
-HIV
-Angiotensin inhibition (ACE I, ARB)

13. Further Investigations
• Case 1
• Direct Renin > 500 uIU/mL
(N range upright 4.4 -46.1 uIU/mL,
supine 2.8 - 39.9 uIU/mL)
• Aldosterone- 27 pg/dL (40-310)
• Case 2
• Direct Renin > 500 uIU/mL
(N range upright 4.4 -46.1 uIU/mL,
supine 2.8 - 39.9 uIU/mL)
• Aldosterone- 35.3 pg/dL (40-
310)

14. Cosyntropin Stimulation test:
Case 1
• Cortisol serum [7 AM]- 12 ug%
• Cortisol serum [7.30 AM]- 20
ug%
• Cortisol serum [8.00 AM]- 24
ug%
• ACTH- 8.1 pg/ml
• Normal Cortisol response
Case 2
• Cortisol serum [7 AM]- 18.4 ug%
• Cortisol serum [7.30 AM]- 29.7
ug%
• Cortisol serum [8.00 AM]- 37.6
ug%
• ACTH- 35.8 pg/ml
• Normal Cortisol response

15. Diagnosis- Aldosterone synthase deficiency

17. Outline
• Aldosterone biosynthesis pathway
• Aldosterone action
• Clinical features of this disease
• Management
• Differentiating from CAH and PHA

18. Aldosterone
synthase
deficiency
ALDOSTERONE is synthesized by
aldosterone synthase (CYP11B2)
zona glomerulosa.

19. Aldosterone
• Aldosterone - renal distal tubules and cortical collecting ducts,
where it acts to increase sodium resorption and potassium excretion
into the urine.

20. Aldosterone synthase deficiency
• Two forms of aldosterone synthase deficiency are described-
deficiency types I (step 1) and II (step 3).
• Aldosterone synthase deficiency type 1 is caused by mutations in
CYP11B2 that completely abolish enzymatic activity.
• Thus usually type 1 deficiency have a more severe phenotype.
• Biochemically - only differences are found in the intermediate steroid
profiles

22. Clinical features
• Most patients present in infancy < 1% enzyme activity
• salt-wasting syndrome- failure to gain weight, dehydration. Hypotension
from hypovolemia, shock, and sometimes death.
• Se Na usually -120 to 130 mEq/L and K of 6.0 to 8.5 mEq/L.
• Biochemical Hallmark- markedly elevated PRA with low aldosterone
• Normal cortisol and sex steroid levels should always be confirmed
• Patients who present after infancy usually have anorexia, mild
dehydration, and abnormal growth.
• Most > 4 years have normal serum electrolyte levels.

23. Treatment
• Treatment of affected infants includes oral sodium supplementation
(sodium chloride 1 to 2 g/d) and fludrocortisone (0.1 to 0.3 mg/d).
• Establishing normal fluid and electrolyte balance will result in good catch-
up growth.
• Mineralocorticoid therapy (fludrocortisone) and sodium supplementation
should be continued and the child should be monitored regularly
throughout childhood.
• Older patients can be treated with fludrocortisone alone.

24. Differentiating factors
Aldosterone synthase deficiency
1. No hyperpigmentation of
genitalia
2. Elevated renin levels
3. Low aldosterone levels
4. Cortisol normal, Synacthen
test response normal
5. Normal serum concentrations
of 17-hydroxyprogesterone
CAH
1. Masculinized genitalia due to
excess secretion of adrenal
androgens
2. Elevated renin levels
3. Low aldosterone levels
4. Cortisol low, Synacthen test
response abnormal
5. Elevated serum
concentrations of 17-
hydroxyprogesterone
Pseudohypoaldosteronism
1. Genitalia normal
2. Low renin levels
3. High aldosterone levels
4. Cortisol normal
5. Normal 17-
hydroxyprogesterone

25. Case reports:
• First reported in the early 1960s (Russell et al 1963)
• The largest number of cases identified subsequently have been
Iranian Jews from the city of Isfahan (Rosler 1984).
• No case reports from India so far.

26. GENETICS
CYP11B2
Autosomal recessive

27. What happened to our patients ?
CASE 1
• 1 year 5 months old girl
• Rx: Tab. Fludrocort 125 mcg BD
• 1600 gram gain over 5 months
• Last Na-138, K-4
• Catching up developmentally
• Walks with support
• Scribbles
• CASE 2
• 6 months 2 weeks old boy
• Rx: Tab. Fludrocort 125 mcg BD
• 2700 gram gain over 2.5 months
• Last Na-141, K-4.5
• Head control
• Turns over

28. Take Home Message
• Careful interpretation of electrolytes in any child with poor growth
and motor developmental delay is important
• If found to have hyponatremia and hyperkalemia – rule out CAH
first.
• Hyperreninemic hypoaldosteronism is seen in Aldosterone synthase
def and is easily amenable to treatment.

29. References
1. Aldosterone synthase deficiency and related disorders.
White PC. Mol Cell Endocrinol. 2004 Mar 31;217(1-2):81-7. Review. PMID: 15134805
2. Klomchan T, Supornsilchai V, Wacharasindhu S, Shotelersuk V, Sahakitrungruang T:
Novel CYP11B2 mutation causing aldosterone synthase (P450c11AS) deficiency. Eur J
Pediatr. 2012, 171: 1559-1562. 10.1007/s00431-012-1792-7.
3. Kondo E, Nakamura A, Homma K, Hasegawa T, Yamaguchi T, Narugami M, Hattori T,
Aoyagi H, Ishizu K, Tajima T: Two novel mutations of the CYP11B2 gene in a Japanese
patient with aldosterone deficiency type 1. Endocr J. 2013, 60: 51-55.
10.1507/endocrj.EJ12-0248.