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Late onset congenital adrenal hyperplasia (LOCAH), also known as non-classic congenital adrenal hyperplasia (NCCAH or NCAH), is a milder form of congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol synthesis that leads to variable degrees of postnatal androgen excess.

The causes of LOCAH are the same as of classic CAH, and in majority the of the cases are the mutations in the CYP21A2 gene resulting in corresponding activity changes in the associated P450c21 (21-hydroxylase) protein enzyme which ultimately leads to excess androgen production. Other causes, albeit less frequent, are mutations in genes affecting other enzymes involved in steroid metabolism, like 11β-hydroxylase or 3β-hydroxysteroid dehydrogenase. It is an autosomal disease and common (0.1%–2% prevalence depending on population). The pathophysiology is complex and not all individuals are symptomatic.

Presentation

Females are diagnosed based on the presentation of symptoms that include hirsutism and menstrual irregularities. While symptoms are usually diagnosed after puberty, children can present with premature adrenarche. Males are generally asymptomatic and diagnosed based on the diagnosis of a female family member. LOCAH affected individuals account for 88% of the often cited 1.7% prevalence of intersex conditions though, from the clinical perspective, LOCAH is not an intersex condition. This disorder was originally characterized in 1957 by French biochemist Jacques Decourt.

The degree of hormonal disorder in patients with LOCAH is relatively mild. Such patients have not been extensively studied. 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 21-hydroxylase. 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.

The following three mutations to the CYP21A2 gene are mostly associated with LOCAH:

• p. V281L (rs6471, CYP21A2*15);
• p.P453S (rs6445, CYP21A2*19);
• p.P30L (rs9378251, CYP21A2*8).

A point mutation in exon 7 of CYP21A2 (p. V281L) accounts for the majority of LOCAH alleles worldwide. Carriers for this mild, p. V281L mutation, resulting in retaining of 20%–50% of 21-hydroxylase activity, are at higher risk of symptoms of androgen excess than carriers of the severe mutations, and had higher adrenocorticotropic hormone (ACTH) stimulated 17α-hydroxyprogesterone.

The particularly mild clinical symptoms of LOCAH such as hyperandrogenism, hirsutism and acne or infertility overlap with other diseases such as polycystic ovary syndrome. Biochemical parameters like 17α-hydroxyprogesterone may not be elevated in very mild cases of LOCAH, and may vary between labs that makes interpretation difficult; and is may not not possible to perform ACTH stimulation tests in all institutions, depending on the availability of the injectable ACTH medication. This is why a comprehensive CYP21A2 genotyping (rather than variant-specific assays alone) is a good way to exclude/confirm 21-hydroxylase deficiency and heterozygosity (carrier) status.

Diagnosis

LOCAH differs from classic congenital adrenal hyperplasia 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. 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 sometimes diagnosed during an evaluation for oligomenorrhea or amenorrhea and infertility. However, an estimated 90% of women with LOCAH never receive a diagnosis. Once they start trying to conceive, roughly 83% of women with known LOCAH become pregnant within 1 year, with or without glucocorticoid therapy. Such women have consistently been found to be at increased risk for miscarriage.

The diagnostic procedure varies according to the specific enzyme deficiency causing LOCAH and the precise serum androgen levels required for diagnosis are the subject to variance from different measurement methods, refinement in specific cases and are under active research. The ACTH stimulation protocols are described in Kurtoğlu and Hatipoğlu.

21-Hydroxylase deficiency

Screening

The condition 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. 17-OHP is one of the markers of the 21-hydroxylase enzyme activity. 17-OHP between 1.7 and 3.0 ng/mL is sufficient for diagnosis while higher levels suggest further investigation. Randomly timed measurements of 17-OHP have not been shown to be useful for screening since they are often normal and are known to be very high in the luteal phase of the female menstrual cycle. After basal levels have been measured, confirmation is done by administering ACTH, and comparing 17-OHP pre and post test. 17-OHP levels over 10 ng/mL at the 60th minute post stimulation is considered diagnostic for LOCAH.

Androgen backdoor pathway

In 21-hydroxylase deficiency, especially in mild cases (LOCAH), androgen "backdoor" pathway may be the reason of androgen excess. In this pathway, 17α-hydroxyprogesterone is a main source for androgens, with roundabout of testosterone as an intermediate product. This leads to elevated levels of various androgens, including 5α-dihydrotestosterone as a final product of the pathway, however, the levels of testosterone may be normal. Unlike testosterone and androstendione, some androgens produced by the "backdoor" pathway, including 5α-dihydrotestosterone, cannot be converted by aromatase into estrogens. When 17α-hydroxyprogesterone levels raise due to lack of 21-hydroxylase (which should have converted it to 11-deoxycortisol), α-androstanediol, precursor of the 5α-dihydrotestosterone, is produced from 17α-hydroxyprogesterone, with various intermediate products that include 3α,5α-17-hydroxyprogesterone and androsterone. Even a mild increase in 17α-hydroxyprogesterone may be sufficient to activate this "backdoor" pathway.

Not all final and intermediate products of the androgen "backdoor" pathway have been studied in vivo, and not all source substrates are elucidated, there may be different intermediate paths. What is well known in vivo is that the main substrate of the "backdoor" pathway is 17α-hydroxyprogesterone that eventually reaches 5α-dihydrotestosterone with omission of testosterone as an intermediate step. In vitro studies suggest that another source product of the androgen backdoor pathway is progesterone which due to 21-hydroxylase deficiency is converted to 11β-hydroxyprogesterone by the steroid 11β-hydroxylase (CYP11B1) enzyme. There are multiple studies conducted since 1987 that demonstrate increased in vivo levels of 11β-hydroxyprogesterone in congenital adrenal hyperplasia. In vitro studies suggest that excess of 11β-hydroxyprogesterone within the androgen "backdoor" pathway produces additional potent androgens like 11-ketodihydrotestosterone and 11-ketoandrosterone. The 11-oxyandrogens pathway through which androstenedione is converted to 11β-hydroxyandrostenedione and then to 11-ketotestosterone and 11-ketodihydrotestosterone is also significant in LOCAH.

This "backdoor" pathway is not always considered in the clinical evaluation of patients with hyperandrogenism, so this may be a source of diagnostic pitfalls and confusion.

11-Hydroxylase deficiency

The activity of 11β-hydroxylase can be determined by observing the basal 11-deoxycortisol level. A level over 10 ng/mL, indicates followup with ACTH stimulation test. The 60th minute post-stimulation 11-deoxycortisol levels higher than 18 ng/mL are diagnostic of LOCAH.

3β-Hydroxysteroid dehydrogenase deficiency

The activity of 3β-hydroxysteroid dehydrogenase can be determined by observing the basal 17α-hydroxypregnenolone level. A level above 30 ng/mL and 17α-hydroxypregnenolone/cortisol ratio above 10 SD are diagnostic of LOCAH.

Management

Management and treatment of LOCAH is case specific and the application of glucocorticoid treatment is not standard as it is in classic CAH. Recent reviews emphasize treatment that is specific to each case rather than merely abnormal hormone levels. LOCAH is not a life-threatening medical condition and the risks of treatment given prenatally or to asymptomatic children outweigh potential benefits. In appropriate cases, glucocorticoids (usually hydrocortisone in children) are administered to suppress secretion of hypothalmic corticotropin releasing hormone (CRH) and pituitary ACTH which will reduce serum concentrations of adrenal sex steroids. Some of the main considerations in treatment include the watchful waiting of symptom severity as well as adverse responses to exogenous glucocorticoids seen in patient bone density, height and weight. For women, an oral contraceptive pill and spironolactone or cyproterone acetate, are alternatives to glucocorticoids for managing symptoms of androgen excess.

Incidence

According to haplotype association studies, the prevalence of LOCAH in the general white population is estimated to be 1:500 to 1:1000, but in people with a high rate of marriage between relatives, the prevalence rate is as high as 1:50 to 1:100. A 2017 CYP21A2 genotype analysis predicts that the total frequency of LOCAH in the US caucasian population is about 1:200 (95% confidence level, from 1:100 to 1:280).

References

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• Adrenal gland disorders
• Autosomal recessive disorders
• Congenital disorders of endocrine system
• Endocrine-related cutaneous conditions