congenital adrenal hyperplasia

Last edited 04/2021 and last reviewed 08/2021

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders.

Congenital adrenal hyperplasia is a metabolic disorder related to enzymatic defects in the biosynthesis of cortical steroids. Typically the defects are inherited in an autosomal recessive manner, and within a particular family all inherit the same enzyme deficiency (1).

Two principal effects result from the enzyme deficiency:

• deficient cortisol and/or aldosterone production
• excess precursor steroids

In response, there is increased ACTH secretion from the anterior pituitary producing adrenocortical hyperplasia.

If left undiagnosed and untreated, CAH can cause high morbidity and mortality. CAH manifests with a range of clinical and biochemical phenotypes(3).

• these are commonly categorised into severe (classic) or mild (non-classic) forms

At least eight distinctive clinical syndromes are recognised but the majority of cases are attributed to:

• 21-hydroxylase deficiency (over 90%) (4)
  • 21-OHD can be further subdivided into 3 variants (3):
    • 1) classic salt wasting (SW)
      • classic salt-wasting accounts for between 70-80% of all cases of 21-OHD and is the most severe
      • causes a life-threatening salt-wasting crisis commonly within the second week after birth and is also characterised by virilisation of female external genitalia
      • severe outcomes associated with this form of CAH may include death, hospitalisation, and other complications such as shock, dehydration and vomiting
    • 2) classic simple virilising (SV)
      • in the simple virilising form, female patients present with virilised external genitalia but with no clinically apparent salt loss. After birth, the excess androgen presence leads to rapid skeletal growth and premature puberty in all children
    • 3) non-classic (NC)
      • non-classic variant may not be detected until later in life and there may be no symptoms
      • nonetheless, female patients may exhibit hyperandrogenism, as well as milder symptoms such as short adult stature, premature pubarche or accelerated bone maturation (5)
    • it has been suggested that 21-hydroxylase deficiency may be a continuum of phenotypes rather than a number of distinct phenotypical entities(6) 
• 11-beta-hydroxylase deficiency (approximately 5%)

The deficiency forms of CAH which are associated:

• with male pseudohermaphrodite include 21alpha-hydroxylase and to a lesser extent 11-beta-hydroxylase
• with female pseudohermaphrodite include 17alpha-hydroxylase, 17,20 lyase, 3beta-hydroxysteroid dehydrogenase, and cholesterol 20,22 desmolase;
• while CAH forms which are associated with hypertension include 17alpha-hydroxylase and 11beta-hydroxylase deficiency (2)

Reference:

• Ogilvy-Stuart A.Endocrinology of the neonate, BJHM 1995;54(5): 207-11.
• Honour JW. Diagnosis of diseases of steroid hormone production, metabolism and action. J Clin Res Pediatr Endocrinol 2009;1(5):209-226
• El-Maouche D, Arlt W, Merke DP. Congenital adrenal hyperplasia. Lancet. 2017;390(10108):2194-210
• Fox DA, Ronsley R, Khowaja AR, Haim A, Vallance H, Sinclair G, et al. Clinical Impact and Cost Efficacy of Newborn Screening for Congenital Adrenal Hyperplasia. Journal of Pediatrics. 2020;220:101-8.e2.
• Speiser PW, Arlt W, Auchus RJ, Baskin LS, Conway GS, Merke DP, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an endocrine society clinical practice guideline. 2018;103(11):4043-88.
• Huynh T, McGown I, Cowley D, Nyunt O, Leong GM, Harris M, et al. The clinical and biochemical spectrum of congenital adrenal hyperplasia secondary to 21-hydroxylase deficiency. 2009;30(2):75.