P450-Side-Chain Cleavage Deficiency

Cytochrome P450 is an enzyme that contributes to the production of steroids by the adrenal glands, gonads (testes and ovaries) and placenta. P450-Side-Chain Cleavage Deficiency is a Variation of Sex Characteristic (VSC)/Differences of Sex Development (DSD) characterised by a defect in this enzyme that reduces the production of steroids (cortisol, aldosterone, and sex hormones). The clinical picture can be variable, as there are also non-classical, late-onset forms characterised by partial enzyme activity.
In the most severe forms, cortisol deficiency usually manifests at birth as a result of a complete lack of activity of the enzyme, and requires urgent medical attention: the adrenal crisis leads to dehydration and loss of sodium to the point of shock.
In the case of partial activity of the enzyme, the inability to establish an adequate response to stress conditions will be observed. Deficiency of sex hormones in individuals with karyotype 46,XY causes poor virilisation of the external genitalia, ranging from micropenis to perineoscrotal hypospadias (external opening of the urethra in a location different from usual) and, in severe cases, bifid scrotum (split in two). Conversely, subjects with karyotype 46,XX exhibit virilisation of the external genitalia and large ovarian cysts.

Genetic traits
P450-Side-Chain Cleavage Deficiency is caused by a mutation in the CYP11A1 gene located on chromosome 15. Transmission is autosomal recessive, which means that for the gene variation to occur in the individual, it must be inherited from both parents. Individuals who have inherited the gene variation from only one parent will show no manifestation of P450-Side-Chain Cleavage Deficiency, although they may still transmit this variation to their offspring.

Identification
Laboratory tests show high levels of adrenocorticotropic hormone (ACTH) and low levels of cortisol, aldosterone and sex hormones, associated with electrolyte disturbances, e.g., hyponatremia (low blood sodium levels) and hyperkalemia (high blood potassium levels). Imaging techniques (ultrasound, MRI) can show a reduction in the volume of the adrenal glands. In any case, diagnostic confirmation is obtained through molecular analysis by searching for mutations in the CYP11A1 gene.

Medical options
The acute adrenal crisis requires prompt therapy immediately after birth with hydrocortisone and fludrocortisone, like in other forms of adrenal insufficiency. A sodium chloride supplement may also be necessary in the first years of life.
Owing to the deficit in sex hormone production typical of this variation, replacement therapy with oestrogen/testosterone will be required during puberty to allow the development and maintenance of secondary sexual characteristics.
Regarding the presence of atypical genitalia, various medical and/or surgical strategies can be implemented. In any case, partially reversible or irreversible interventions must be postponed to when the person can express their informed consent.

Bibliography
Hiort O et al. Homozygous disruption of P450 side-chain cleavage (CYP11A1) is associated with prematurity, complete 46,XY sex reversal, and severe adrenal failure. Journal of Clinical Endocrinology & Metabolism. 2005 Jan;90(1):538-41
Kim CJ et al. Severe combined adrenal and gonadal deficiency caused by novel mutations in the cholesterol side chain cleavage enzyme, P450scc. Journal of Clinical Endocrinology & Metabolism. 2008 Mar;93(3):696-702

Further Links
Orphanet. CYP11A1 - cytochrome P450 family 11 subfamily A member 1