[5] The causes of LOCAH are the same as of classic CAH, and in the majority of the cases are the mutations in the CYP21A2 gene resulting in corresponding activity changes in the associated P450c21 (21-hydroxylase) enzyme which ultimately leads to excessive androgen production.
[13][14] Flatter diurnal cortisol slopes contribute to stress-related dysregulation of central and peripheral circadian mechanisms with negative health outcomes.
[30][31][32] Rare presentation of testicular adrenal rest tumors[33][19][27] which do not affect fertility and do not require regular ultrasound examinations of the scrotum[1] is also possible.
[38][36][35] Carriers for this mutation retain 20%–50% of 21-hydroxylase activity,[39][23] but are at higher risk of symptoms of androgen excess than carriers of the severe mutations,[40] and had higher adrenocorticotropic hormone (ACTH) stimulated 17α-hydroxyprogesterone,[41] suggesting that the mutant protein V281L enzyme co-expressed with the wild-type (healthy) enzyme resulted in an apparent dominant negative effect on the enzymatic activity.
[42] The particularly mild clinical symptoms of LOCAH such as hyperandrogenism, hirsutism and acne or infertility overlap with other diseases such as polycystic ovary syndrome.
[43] Genetic testing can be used to exclude false positive diagnosis based on biochemical parameters alone, even with ACTH stimulation, since elevated 17-OHP levels may be also caused by ovarian or adrenal tumors, rather than by the variants in the CYP21A2 gene.
[44] Originally characterized in 1957 by French biochemist Jacques Decourt,[45] LOCAH differs from classic CAH in that it does not cause atypical neonatal genital morphology, is not life-threatening and presents after birth.
[46] Many individuals (both male and female) present no symptoms during childhood and adolescence and only become aware of the possibility of LOCAH due to the diagnosis of another family member.
[46][51] The condition of 21-hydroxylase deficiency is screened by measuring serum levels of 17α-hydroxyprogesterone (17-OHP) in the morning and between day 3 and 5 of the menstrual cycle (for females) to reduce the possibility of false positive results.
[23][46] Most research on the biochemical diagnosis of LOCAH relied on direct immunoassays, such as radioimmunoassays or time-resolved fluorescence assay to measure 17-OHP, therefore, cross-reactivity and reliability problems of these methods might have caused differences in the 17-OHP cutoff values recommended, so the use of liquid chromatography–mass spectrometry aims to improve the accuracy of 17-OHP measurement and increase diagnostic quality of LOCAH.
[54] This backdoor pathway is not always considered in the clinical evaluation of patients with hyperandrogenism conditions such as LOCAH and may be a source of diagnostic pitfalls and confusion.
[1] Some of the main considerations in treatment include the watchful waiting of symptom severity as well as adverse responses to glucocorticoids administered as drugs, seen in patient bone mineral density, height and weight.
[2][38] According to a 2017 meta-analysis, the prevalence of LOCAH among women with signs and symptoms of androgen excess is 4.2% globally, and between 1% and 10% depending on the ethnicity of the population being studied.
[23] Anne Fausto-Sterling, an American sexologist, in a 2000 book "Sexing the Body" came up with an estimate that people with intersex conditions account for 1.7% of the general population.
[59] Leonard Sax, an American psychologist and a family physician, criticized these figures in a review published in 2002 in The Journal of Sex Research, stating that from the clinician's perspective, LOCAH is not an intersex condition.