ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Hum Genet. 2018; 137(11–12): 955–960.

Patients with Congenital adrenal hyperplasia (CAH) suffer from multiple comorbidities, including mental illness. Studies that investigated the prevalence of psychiatric disorders in patients with CAH showed that any psychiatric diagnosis were more common in CAH subjects compared with population controls. In particular, the risk of alcohol misuse was increased in females with CAH compared with controls, and appeared most common among the girls and women with the most severe null genotype. The risk of stress and adjustment disorders was doubled compared with female population controls. Furthermore, suicidality, other psychiatric disorders (excluding suicidality), and alcohol misuse were increased in males with CAH compared with controls. There was no increased risk for any neurodevelopmental disorder.

CYP21A2, the gene mutated in, lies within the major histocompatibility complex within a region (RCCX) that is error prone during meiosis. Neighbouring CYP21A2 are genes that encode the complement component 4 isotypes, C4A and C4B, which are implicated in a variety of diseases, both immune related and psychiatric.

This study aimed to evaluate C4A and C4B copy number variation in patients with CAH in relation to psychiatric morbidity and autoimmunity. The authors determined comorbidity, copy numbers of C4A and C4B in patients with CAH and carrier relatives, and evaluated serum C4 concentrations. Only 30% of subjects had the expected two copies in each of the two C4 genes. High C4A copy number was associated with increased risk of an externalizing psychiatric condition. C4B copy number determined total C4 copy number and serum C4 concentrations, negatively correlated with carriership of a 30-kb deletion, and positively correlated with carriership of the p.V281L variant. No association was found between C4 copy number and autoimmune disease. This study provides evidence that RCCX genotype as it relates to C4 may be an additional risk factor for psychiatric comorbidity in patients with CAH.