A Case presentation of a well developed young

A Case presentation of a well developed young male TALIA NOVOS

PRESENTATION A 6 YEAR OLD BOY WAS REFERRED TO A PAEDIATRIC ENDOCRINOLOGIST WITH A SUSPECTED GROWTH DISORDER BECAUSE HE WAS SUBSTANTIALLY TALLER THAN THE OTHER PUPILS IN HIS CLASS

PATIENT HISTORY • 6 YEAR OLD BOY • SUBSTANTIALLY TALL FOR HIS AGE (>99 th percentile) • GOOD HEALTH (weight at 50 th percentile) • NORMAL DELIVERY AT TERM • PERFORMING WELL AT SCHOOL • BOTH PARENTS OF AVERAGE HEIGHT. • NO MEDICATION • PENILE LENGTH AND VOLUME INCREASED (TANNER STAGE 2), BUT TESTES NORMAL FOR AGE.

INITIAL INVESTIGATION Dipstick tests were ordered to investigate: Glycosuria (Diabetes) Proteinuria (Kidney disease) Hematuria or hemoglobinuria (Golumerular, tubulointerstitial or post renal disease. As well as hemolytic anemia etc). Plasma Renin activity (PRA) was ordered. PRA is sometimes measured, in case of certain diseases which present with hypertension.

INITIAL INVESTIGATION RESULT DIPSTICK URINALISIS REFERNCE INTERVAL GLUCOSE NEGATIVE PROTEIN NEGATIVE BLOOD NEGATIVE PLASMA RENIN ACTIVITY 18. 6 ng/ml/h (22. 7 pmol/h/ml) 1. 4 ng/m. L/hour (mean) (5)

INITIAL INVESTIGATION NORMAL Slightly ELEVATED LOW SERUM RESULT REF INTERVAL SODIUM 137 mmol/L 135 – 145 mmol/L POTASSIUM 3. 7 mmol/L 3. 6 – 5. 1 mmol/L UREA 6. 7 mmol/L 2. 9 -7. 1 mmol/L CREATININE 47 µmol/L 30 -60 µmol/L TESTOSTERONE 2. 8 nmol/L 0. 1 - 1. 04 nmol/L ALDOSTERONE 771 pmol/L 28 -666 pmol/L (1) CORTSIOL 41 nmol/L 69 - 632 nmol/L

WORKING DIAGNOSIS • Low Cortisol • Normal sodium • Slightly elevated Aldosterone =? PROCEDE WITH ADRENOCORTICOTROPIC HORMONE (ACTH) STIMULATION TEST

Why do we do an ACTH stimulation test? ACTH stimulation tests are performed to demonstrate the functional capacity of adrenal glands to produce cortisol and to test the abnormal accumulation of precursor steroids.

How do we do an ACTH stimulation test? A baseline measurement of cortisol (and in this case 17 -OHP androstenedione) is taken. Low dose synthetic ACTH (Synacthen) is administered and measurements of cortisol are taken at 30 and 60 minutes.

WORKING DIAGNOSIS RESULTS OF ACTH STIMULATION TEST: TIME (min) CORTISOL (nmol/L) 17 -OHP (nmol/L) ANDROSTENEDIONE (nmol/L) 0 24 >300 13. 2 30 35 >300 16. 1 60

FINAL DIAGNOSIS CONGENITAL ADRENAL HYPERPLASIA DUE TO 21 -HYDROXYLASE DEFICIENCY

What is Congenital Adrenal Hyperplasia Congenital Adrenal hyperplasia (CAH) is a an inherited disorder characterized by a specific enzyme deficiency in the steroid pathway. Over 90% of cases of CAH are caused by a 21 -hydroxylase deficiency (21 -OHD).

What is Congenital Adrenal Hyperplasia? CAH 21 -hydroxylase (21 -OHD) 3β-hydroxysteroid dehydrogenase (3β-HSD) 11βhydroxylase (11 -β-OHD)

The Steroid Pathway and 21 -Hydroxylase Deficiency

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What is 21 -hydroxylase deficiency

Androgen Excess Conversions of 17 -hydroxyprogesterone (17 -OHP) to 11 -deoxycortisol is impaired Progesterone (P 4) to deoxycorticosterone, are impaired. Elevated 17 -OHP, Progesterone, and Androstenedione concentrations are typically found (As seen in our patient).

The Steroid Pathway and 21 -Hydroxylase Deficiency

21 -OHD at the molecular level (7)

Types of 21 -hydroxylase deificency • There are 2 types of 21 -OHD: - Classic 1) Salt wasting 2) Simple virilizing - Non Classic

Clinical Presentation of non salt wasting CAH Children may present with: premature pubarche (i. e. the development of pubic hair, axillary hair, and/or increased apocrine odor prior to age 8 years in girls and age 9 years in boys). Tall structure due to accelerated linear growth velocity, and advanced skeletal maturation, however this can promote premature epiphyseal fusion, leading to short stature in adults (more prominent in classic CAH).

Clinical presentations: Females • During adolescence and adulthood, an ascertainment bias favors the diagnosis in females due to the nature of the hyperandrogenic symptoms. Symptoms include: • Hirsutism • Acne • Alopecia • Anovulation • Menstrual dysfunction.

Clinical presentations: Females • Adult females, the clinical presentation may be • • indistinguishable from Polycistic ovaries syndrome (PCOS) or idiopathic hirsutism. Other factors associated with increased risk for metabolic consequences include Obesity Hypertension Insulin resistance.

Clinical Presentations: Males In boys the abnormality may not be suspected until signs of precocious puberty or accelerated growth are present. Phallic enlargement with prepubertal testes may be noted

Treatment Generally, treatment plans aim at: • Glucocorticoid treatment to replace the lack of cortisol and treat androgen excess Other treatment options for patients without cortisol deficiency (Non-classic) can include: • Oral contraceptives can be used to combat oligomenorrheia, acne, and mild hirsutism. • Anti-androgens (e. g. flutamide, cyproterone acetate, or finasteride) can be used to treat hirsutism and alopecia in females. • Women seeking fertility may benefit from the use of ovulatory agents (clomiphene or menotropins). • Fludrocortisone for salt wasting forms to replace aldosterone.

Androgen Panel by LCMSMS

Bibliography 1. Pediatric Reference Intervals 6 th edition, AACC Press. Edited by Steven J Soldin et al. 2. 21 -Hydroxylase Deficiency. Ron S. Newfield and Maria I. New. Department of Pediatrics, the 3. 4. 5. 6. 7. new york Hospital –Cornell Medical Centre. , New York. Annals of the New York Academy of Sciences, Volume 816, Jun 1997. Tietz fundamentals of Clincal Chemistry. Plasma renin activity and aldosterone concentration in children. M J Dillon, Jennifer M. Ryness. British Medical_Journal, 1975, 4, 316 -319 Mayo laboratories: http: //www. mayomedicallaboratories. com/ Non classic Congenital Adrenal Hyperplasia: Selma Feldman Witchel and Ricardo Azziz. International Journal of Pediatric Endocrinology 2010, 2010: 625105 www. genetics 4 medics/congenital-adrenal-hyperplasia. html