StAR Deficit (Steroidogenic Acute Regulatory protein)

StAR (Steroidogenic Acute Regulatory protein) assists in transferring cholesterol across the mitochondrial membrane, initiating steroid production. Malfunctioning of this protein leads to congenital lipoid adrenal hyperplasia (LCAH), characterised by a severe deficiency in adrenal and gonadal steroid hormone production (cortisol, aldosterone, sex hormones). As a consequence, the adrenal glands undergo hyperplasia, and intracellular cholesterol accumulates.
LCAH is a Variation of Sex Characteristics (VSC)/Difference of Sex Development (DSD) extremely rare in Europe and America, and has an approximate frequency of 1 in 300,000 births in Asian countries.
Clinically, LCAH manifests early, around birth, with symptoms of salt-wasting adrenal insufficiency such as vomiting, diarrhoea, dehydration, and hypotension. In individuals with a 46,XY karyotype, the external genitalia are typically female, sometimes slightly masculinized, and the testicles are often cryptorchid (undescended into the scrotum). The ovarian function is usually partially preserved, which enables the onset of puberty and menarche (first menstruation), but later, LCAH may lead to hypergonadotropic hypogonadism (ovarian insufficiency).
There are also non-classic forms of LCAH, resulting from a partial inactivation of StAR, with no impact on the external genitalia, but adrenal insufficiency occurring later in adulthood.

Genetic Traits
Congenital lipoid adrenal hyperplasia is caused by mutations in the gene encoding StAR, located at the 8p11.2 locus. Transmission is autosomal recessive. This means that for the gene variation to occur, it must be inherited from both parents. Individuals who have inherited the gene variation from only one parent will not exhibit LCAH in any way, but they may still pass it on to their offspring.

Identification
Hormonal diagnosis involves elevated levels of adrenocorticotropic hormone (ACTH) and renin, along with decreased levels of cortisol, aldosterone, and sex hormones. Through imaging techniques like ultrasound and magnetic resonance, gonads and internal genitalia can be located and studied, thus aiding in diagnosis. Molecular analysis with gene sequencing confirms the condition.

Medical Options
In classic LCAH, because of acute adrenal insufficiency, medical therapy must be initiated promptly after birth. This includes replacement therapy with glucocorticoids (typically hydrocortisone) and mineralocorticoids (fludrocortisone). A sodium chloride supplement may also be necessary.
For individuals with a 46,XY karyotype, genital or gonadal surgery should be postponed to allow exploration of gender identity. Although in the scientific literature there are no data specifically related to people with this variation, if cryptorchid testicles are present, the risk of testicular cancer increases, and preventive strategies must be considered. Orchidectomy (testicle removal) can be an option with the individual's informed consent and alignment with their gender identity. Annual monitoring with ultrasound or magnetic resonance imaging is advised to promptly identify potential malignant testicular lesions.
In the classic form, sex hormone replacement therapy is required after puberty. People with a 46,XX karyotype go through puberty and menarche, but their menstrual cycles are typically without ovulation, leading to infertility. Counselling regarding fertility preservation options is recommended.

Bibliography
Bose HS et al. The pathophysiology and genetics of congenital lipoid adrenal hyperplasia. The New England journal of medicine. 1996 Dec 19;335(25):1870-8
Ishii T et al. Clinical Features of 57 Patients with Lipoid Congenital Adrenal Hyperplasia: Criteria for Nonclassic Form Revisited. The Journal of clinical endocrinology and metabolism. 2020 Nov 1;105(11):dgaa557

Further Links
Orphanet. Congenital lipoid adrenal hyperplasia due to STAR deficency
Online Mendelian Inheritance in Man (OMIM). LIPOID CONGENITAL ADRENAL HYPERPLASIA; LCAH