ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: J Clin Endocrinol Metab. 2019; 104(12): 6148–6154. PMID: 31393570.

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency has an incidence of 1 in 10 000 to 20 000 in most populations. It is one of the most common monogenic autosomal recessive disorders (1). It has been suggested that the condition is common because it may confer a survival advantage to carriers, 1 in 15 000 in most populations (2). The hypothesized mechanism is that the increased and more prompt cortisol response to stress (due to an upregulated HPA-axis) seen among CYP21A2 mutation carriers enables a more rapid return to homeostasis. Previously, it was shown that CYP21A2 mutation carriers (parents of children with CAH) are more likely to have a psychiatric diagnosis both before and after the birth of the child with CAH, indicating less vulnerability to stress (3).

Here, Nordenström et al. investigated the mortality and the cause of death in obligate CYP21A2 mutation carriers (i.e. parents of children with CAH). In particular, infection as the cause of death was investigated, since infectious disease from an evolutionary perspective has been a threat to mankind, and a more effective stress response or resistance to infections could confer a survival advantage explaining the high percentage of CYP21A2 mutation carriers in most populations.

A total of 1143 obligate carriers of a CYP21A2 mutation were compared with population controls matched for sex and age (100 controls per carrier). Mortality and cause of death were investigated via the Swedish Cause of Death Registry. All-cause mortality was lower in CYP21A2 mutation carriers than in the general population (Hazard Ratio, HR 0.79, P =0.002), with a slightly stronger protective effect in carriers of more severe mutations (HR 0.65, P =0.003) than carriers of simple-virilizing CAH mutations (HR 0.71, P =0.02). Parents of children with non-classical CAH or CAH of unknown severity did not differ from population controls, indicating that the severity of the mutation (and hence the cortisol response) may be important. In all groups, women had a lower HR than men, as seen in the general population. Risk of death from infection was lower in carriers (HR 0.65, P <0.01), in particular death from pneumonia (HR 0.22, P =0.03), but not from sepsis, erysipelas, or hepatitis. In addition, no difference in deaths from cancers or cardiovascular disease was detected.

In summary, the more efficient cortisol response to somatic and psychological stress in carriers of a CYP21A2 mutation may represent a survival advantage, in particular from death caused by infections. This protection may contribute to the high incidence of CYP21A2 mutation carriers seen worldwide.

References:

1. Speiser PW, Arlt W, Auchus RJ, Baskin LS, Conway GS, Merke DP, Meyer-Bahlburg HFL, Miller WL, Murad MH, Oberfield SE, White PC. Congenital adrenal hyperplasia due to steroid 21- hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018; 103(11): 4043–4088.

2. Witchel SF, Lee PA, Suda-Hartman M, Trucco M, Hoffman EP. Evidence for a heterozygote advantage in congenital adrenal hy- perplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab. 1997; 82(7): 2097–2101.

3. Charmandari E, Merke DP, Negro PJ, Keil MF, Martinez PE, Haim A, Gold PW, Chrousos GP. Endocrinologic and psycho- logic evaluation of 21-hydroxylase deficiency carriers and matched normal subjects: evidence for physical and/or psychologic vulnerability to stress. J Clin Endocrinol Metab. 2004; 89(5): 2228–2236.