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. Diagnosis
Originally characterized in 1957 by French biochemist Jacques Decourt, LOCAH differs from classic CAH in that it does not cause atypical neonatal genital morphology, is not life-threatening and presents after birth. Unlike classic CAH, LOCAH generally cannot be reliably detected with neonatal screening. 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. It is thought that 90% of women with LOCAH never receive a diagnosis. In young females, premature pubarche is generally the first symptom to present. The earliest known diagnosis was in a 6 month old female who developed pubic hair. Additional symptoms include acne, menstrual irregularities and hirsutism in females as well as alopecia in males. LOCAH is often misdiagnosed as polycystic ovarian disease (PCOS).LOCAH is often diagnosed in the context of infertility assessment in women. During the follicular phase of the menstrual cycle, progesterone accumulates along with 17α-hydroxyprogesterone which can thin the endometrium and change cervical mucus in a manner similar to the effect of progestogen contraceptives, interferes with the normal menstrual cycle, which can lead to oligomenorrhea or amenorrhea and impairs sperm penetration. Abnormal endometrial development leads to decreased uterine receptivity, which also contributes to infertility.
Flatter diurnal cortisol slopes contribute to stress-related dysregulation of central and peripheral circadian mechanisms with negative health outcomes.Due to hyperandrogenism, females may present with symptoms like hirsutism, oligomenorrhea, acne, infertility, and male-pattern baldness.Males are generally asymptomatic, but may present with acne, early balding, chronic prostatitis, chronic pelvic pain syndrome, and very rarely, testicular adrenal rest tumors.While symptoms are usually diagnosed after puberty, children may present with premature adrenarche.The degree of hormonal disorder in patients with LOCAH is relatively mild. However, alterations in the hypothalamic–pituitary–adrenal axis are present even in this mild form of the disease and might contribute to psychiatric vulnerability. Molecular genetics
LOCAH is most commonly attributed to mutations in the CYP21A2 gene, which encodes the 21-hydroxylase enzyme. Cases of LOCAH due to deficiencies in other enzymes that are known causes of CAH (3β-hydroxysteroid dehydrogenase, steroid 11β-hydroxylase, etc.) are rare and have no established prevalence estimates.Several severe mutations have been associated with LOCAH: the deletion of the CYP21A2 gene, small gene conversions, the p. I172N (rs6475, c.518T>A, CYP21A2*11) mutation, the c.293-13A/C>G (rs6467, CYP21A2*9) mutation, and the p.Gln318Stop (p.Q318X, rs7755898, c.952C>T, CYP21A2*17) mutation. Besides that, LOCAH due to 21-hydroxylase deficiency can be caused by duplications of CYP21A1P pseudogene and C4B gene. Due to the high degree of homology between the CYP21A2 gene and the CYP21A1P pseudogene, and the complexity of the locus, research on the sequencing level can be difficult.