Congenital Adrenal Hyperplasia

Vijayakumar Madhava
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21 Hydroxylase Deficiency
21 hydroxylase deficiency is due to mutations in CYP21A2 gene and is one of the most common inborn errors of metabolism. Because of newborn screening programs, cases are being diagnosed in the new born periods and due to efficient management, majority of cases are reaching adulthood.
In the severest form, there is a complete block at the level of conversion of progesterone to deoxy corticosterone (DOC) which results in aldosterone deficiency causing severe hyponatremia, hyperkalemia and acidosis. Block at the level of 17 hydroxyprogesterone to 11 deoxycortisol results in reduced cortisol production resulting in hypoglycemia. If this condition is not diagnosed in a neonate, associated hypotension, shock and cardiovascular collapse result in death of the affected child.
In utero, this inappropriately produced testosterone causes varying degree of virilization of external genitalia in a girl child. The degree of virilization ranges from mild clitoromegaly with or without fusion of posterior labial folds to complete labioscrotal fusion with urethra situated in the enlarged clitoris. They present with atypical genitalia and create problems in sex assignment at birth. They have normally developed uterus, fallopian tubes and ovaries.

Table 3: Serum 17 – hydroxyprogesterone levels in normal children (Adapted from Harriet lane)
Age Baseline (ng/d L) 60 minute post ACTH stimulation (ng/dL)
Cord blood 2000  
Neonate ( > 48 hours) 420  
Infancy ( 1-12 months) 11-170 85-465
1-5 yr 4-115 50-350
6-12 yr 7-69 75-220
Adolescents boys(Tanner ii,iii) 12-130 69-310
Adolescent boys (Tanner iv, v) 51-190 105-230
Adolescent girls ( Tanner ii.iii) 18-220 80-420
Adolescent girls ( Tanner iv,v) 36-200 80-225


Neonatal screening for CAH with 17 OHP assay have shown that the incidence of classic CAH is 1 in 14,000. Even though exact data are not available, incidence of non Classic CAH is much higher.

In CAH, clinical presentation is variable depending upon the severity of the limiting enzyme deficiency. Based on the clinical spectrum, this disease is classified into 3 groups. This classification is arbitrary because they just represent different clinical presentation of the same disease
• Salt wasting CAH
• Simple virilizing CAH
• Non classic CAH

This condition is caused by a complete deficiency of the enzyme 17 hydroxylase ( P450 c 21) and results in complete block in the synthesis of glucocorticoids and mineralocorticoids. Girls present with virilization at birth and this is the most common form of 46 XX DSD. These babies often require resuscitation for the cardiovascular collapse, hypoglycemia, acidosis and electrolyte abnormalities at presentation. Mineralocorticoids and glucocorticoids are replaced. They need periodic monitoring and titration of glucocorticoids and mineralocorticoids. Girls need surgical correction of their atypical genitalia. Many a time boys are diagnosed late during their salt loosing crisis (5th – 15th day of life) or not diagnosed at all resulting in neonatal death due to wrong diagnosis like sepsis or hypoglycemia.

Simple virilizing form of CAH is a milder variety, when compared to salt loosing variety. In girls, presence of atypical genitalia leads to early detection. But males (unless detected by new born screening) may present later when they develop premature pubic, axillary or facial hair or notice increase in phallic growth, inappropriate for their age. Their testicular volume is pre-pubertal, differentiating from central precocious puberty, in which testicular volume increases (> 3ml) due to gonadotropin stimulation.Their linear growth velocity will be above their peers, but they end up as short adults because their bone maturation advances faster resulting in early fusion of epiphyses. In untreated cases, boys will have small testes, delayed puberty and azoospermia because the adrenal androgens produce a negative feedback to hypothalamus, suppressing the pituitary gonadotropins. Once treatment is begun in childhood, this suppression is removed and this occasionally results in central precocious puberty. High concentration of ACTH in a poorly managed child leads in the development of adrenal rests in the testes.

This is a mild form of 21- hydroxylase deficiency. This condition is also called as late- onset CAH. They may present in older children with hirsuitism, virilization, acne, menstrual irregularities or as decreased fertility. They may just present as a normal child with elevated 17- OHP level to ACTH stimulation test (cryptic CAH) and high PRA (Plasma Rennin Activity)

Table 2 : ACTH stimulation test
  • Basal value of 17 OHP and cortisol are measured
  • Synthetic ACTH is administered IV (Dose 0.1 mg in NB, 0.15 mg up to 2 yrs, 0.25 mg in >2 years)
  • Repeat values are measured at 60 minutes
  • Results: in classical CAH, both basal (> 2000 ng/dL) and stimulated (5,000 – 10,000 ng/dL) will be elevated. In non- classical type, normal or mild elevation of basal 17-OHP with high stimulated levels.
  • A complete adrenocortical profile helps to differentiate 21 hydoxylase deficiency from other type of CAH



Compared to 21 hydroxylase deficiency, other varieties of CAH are rare.
CAH due to 11ß hydroxylase may also present with a salt – wasting crisis in new born period since the amount of deoxy corticosterone ( DOC) produced is insufficient to meet the mineralocorticoid requirement in new born period. But the salt wasting episode is less severe when compared with 21 hydroxylase deficiency. But mineralocorticoid requirement is less as the age advances and they develop hypertension.

Table 4 : Comparison of the potency of various steroid preparations
Steroid Anti inflammatory effect Growth retarding effect Salt -retaining (mineralocorticoid) effect
Cortisol (hydrocortisone) 1 1 1
Cortisone 0.8 0.8 0.8
Prednisone/ prednisolone 4 5 0.25
Methyl prednisolone 5 7.5 0.4
Betamethasone 25   0
Dexamethasone 30 80 0
Fludrocortisone 15   200
Triamcinolone 5   0



References
Congenital Adrenal Hyperplasia Congenital Adrenal Hyperplasia 03/18/2016
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