Biology:Late onset congenital adrenal hyperplasia

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Late onset congenital adrenal hyperplasia (LOCAH), also known as nonclassic congenital adrenal hyperplasia (NCCAH or NCAH), is a specific type of congenital adrenal hyperplasia (CAH) that is typically due to mutations in the CYP21A2 gene resulting in mutations and corresponding activity changes in the associated P450c21 (21-hydroxylase) protein which ultimately leads to excess androgen production. It is an autosomal disease and common (0.1%–2% prevalence depending on population[1]). The pathophysiology is complex and not all individuals are symptomatic.

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.[1][2] 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.[3] This disorder was originally characterized in 1957.[4]

Molecular genetics

In the most common cause of CAH, the deficiency of 21-hydroxylase activity impairs or stops the conversion of 17 hydroxyprogesterone (17 OHP) to 11 deoxycortisol and of progesterone to deoxycorticosterone. Three mutations to the underlying CYP21A2 gene (p. V281L, p.P453S, p.P30L) are associated with LOCAH resulting in retaining only 20%–50% of 21-hydroxylase activity. A point mutation in exon 7 of CYP21A2 (p. V281L) accounts for the majority of LOCAH alleles worldwide.[5] Overall, there is a low genotype-phenotype correlation which partially explains the difficulty in diagnosis. Cases of LOCAH due to deficiencies in other enzymes that are known causes of CAH 3β-hydroxysteroid dehydrogenase and 11-hydroxylase are rare and have no established prevalence estimates.[6]

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 CAH, LOCAH generally cannot be reliably detected with neonatal screening.[7] 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.[8] The earliest known diagnosis was in a 6 month old female who developed pubic hair.[9] 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).[10]

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.[11]

21-Hydroxylase deficiency

The condition is screened by measuring serum levels of 17-hydroxyprogesterone (17 OHP) in the morning and between day 3 and 5 of the menstrual cycle (for females). 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 adrenocorticotropic hormone (ACTH) stimulation test, and comparing 17-hydroxyprogesterone pre and post test. 17 OHP levels over 10 ng/mL at the 60th minute post stimulation is considered diagnostic for LOCAH.

11-Hydroxylase deficiency

A basal 11-deoxycortisol level over 10 ng/mL is appropriate for 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

A basal 17α-hydroxypregnenolone level above 30 ng/mL and 17α-hydroxypregnenolone/cortisol ratio above 10 SD are diagnostic of LOCAH.

Management and treatment

Management and treatment of LOCAH is case specific and the application of glucocorticoid treatment is not standard as it is in CAH. Recent reviews emphasize treatment that is specific to each case rather than merely abnormal hormone levels.[12][13][14] LOCAH is not a life-threatening medical condition and the risks of treatment given prenatally or to asymptomatic children outweigh potential benefits.[15][16][17] 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 seen in patient bone density, height and weight.

References

  1. ↑ 1.0 1.1 Speiser, Phyllis W.; Azziz, Ricardo; Baskin, Laurence S.; Ghizzoni, Lucia; Hensle, Terry W.; Merke, Deborah P.; Meyer-Bahlburg, Heino F. L.; Miller, Walter L. et al. (September 2010). "Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline". The Journal of Clinical Endocrinology & Metabolism 95 (9): 4133–4160. doi:10.1210/jc.2009-2631. PMID 20823466. 
  2. ↑ Witchel, Selma Feldman; Azziz, Ricardo (2010). "Nonclassic Congenital Adrenal Hyperplasia". International Journal of Pediatric Endocrinology 2010: 625105. doi:10.1155/2010/625105. PMID 20671993. 
  3. ↑ Sax, Leonard (August 2002). "How common is lntersex? A response to Anne Fausto‐Sterling". Journal of Sex Research 39 (3): 174–178. doi:10.1080/00224490209552139. PMID 12476264. "Reviewing the list of conditions which Fausto-Sterling considers to be intersex, we find that this one condition–late-onset congenital adrenal hyperplasia (LOCAH)–accounts for 88% of all those patients whom Fausto-Sterling classifies as intersex (1.5/1.7 = 88%). From a clinician’s perspective, however, LOCAH is not an intersex condition. The genitalia of these babies are normal at birth, and consonant with their chromosomes: XY males have normal male genitalia, and XX females have normal female genitalia.". 
  4. ↑ DECOURT, J; JAYLE, MF; BAULIEU, E (1957). "[Clinically late virilism with excretion of pregnanetriol and insufficiency of cortisol production].". Annales d'endocrinologie 18 (3): 416–22. PMID 13470408. 
  5. ↑ Hannah-Shmouni, F; Morissette, R; Sinaii, N; Elman, M; Prezant, TR; Chen, W; Pulver, A; Merke, DP (November 2017). "Revisiting the prevalence of nonclassic congenital adrenal hyperplasia in US Ashkenazi Jews and Caucasians.". Genetics in Medicine 19 (11): 1276–1279. doi:10.1038/gim.2017.46. PMID 28541281. 
  6. ↑ Speiser, Phyllis W. (9 August 2008). "Nonclassic adrenal hyperplasia". Reviews in Endocrine and Metabolic Disorders 10 (1): 77–82. doi:10.1007/s11154-008-9097-x. PMID 18690539. "These may include deficiencies of 3β-hydroxysteroid dehydrogenase (encoded by HSD3B2), 11-hydroxylase (CYP11B1), and most often diagnosed, 21-hydroxylase (CYP21A2, also termed CYP21). Because of their rarity, there are no accurate prevalence estimates of nonclassic forms of the two former enzyme deficiency disorders.". 
  7. ↑ Kurtoğlu, Selim; Hatipoğlu, Nihal (7 March 2017). "Non-Classical Congenital Adrenal Hyperplasia in Childhood". Journal of Clinical Research in Pediatric Endocrinology 9 (1): 1–7. doi:10.4274/jcrpe.3378. PMID 27354284. "It is known that NCCAH cases usually cannot be detected during CAH screenings made in the neonatal period.". 
  8. ↑ Livadas, Sarantis; Bothou, Christina (6 June 2019). "Management of the Female With Non-classical Congenital Adrenal Hyperplasia (NCCAH): A Patient-Oriented Approach". Frontiers in Endocrinology 10: 366. doi:10.3389/fendo.2019.00366. PMID 31244776. "In most cases occurring under 8 years of age, the first symptom is premature pubarche.". 
  9. ↑ KOHN, BRENDA; LEVINE, LENORE S.; POLLACK, MARILYN S.; PANG, SONGYA; LORENZEN, FRANZISKA; LEVY, DONNA; LERNER, ALAN J.; RONDANINI, GIAN FILIPPO et al. (November 1982). "Late-Onset Steroid 21-Hydroxylase Deficiency: A Variant of Classical Congenital Adrenal Hyperplasia*". The Journal of Clinical Endocrinology & Metabolism 55 (5): 817–827. doi:10.1210/jcem-55-5-817. PMID 6288753. 
  10. ↑ CHROUSOS, GEORGE P. (1 February 1982). "Late-Onset 21-Hydroxylase Deficiency Mimicking Idiopathic Hirsutism or Polycystic Ovarian Disease". Annals of Internal Medicine 96 (2): 143–8. doi:10.7326/0003-4819-96-2-143. PMID 6977282. 
  11. ↑ Kurtoğlu, Selim; Hatipoğlu, Nihal (7 March 2017). "Non-Classical Congenital Adrenal Hyperplasia in Childhood". Journal of Clinical Research in Pediatric Endocrinology 9 (1): 1–7. doi:10.4274/jcrpe.3378. PMID 27354284. 
  12. ↑ Speiser, Phyllis W. (9 August 2008). "Nonclassic adrenal hyperplasia". Reviews in Endocrine and Metabolic Disorders 10 (1): 77–82. doi:10.1007/s11154-008-9097-x. PMID 18690539. "Treatment should not be instituted merely for elevated hormone levels. Similarly in adults, hormone treatment should be reserved for women who suffer from symptoms of androgen excess not readily remediable by other methods.". 
  13. ↑ Kurtoğlu, Selim; Hatipoğlu, Nihal (7 March 2017). "Non-Classical Congenital Adrenal Hyperplasia in Childhood". Journal of Clinical Research in Pediatric Endocrinology 9 (1): 1–7. doi:10.4274/jcrpe.3378. PMID 27354284. "Treatment should not be instituted merely for elevated hormone levels.". 
  14. ↑ Kelestimur, F (August 2006). "Non-classic congenital adrenal hyperplasia.". Pediatric Endocrinology Reviews : PER 3 Suppl 3: 451–4. PMID 17551465. "NCAH is not characterized by cortisol insufficiency and these patients do not need glucocorticoid replacement before and/or during surgery unless they have been treated chronically with glucocorticoids.". 
  15. ↑ Miller, Walter L.; Witchel, Selma Feldman (May 2013). "Prenatal treatment of congenital adrenal hyperplasia: risks outweigh benefits". American Journal of Obstetrics and Gynecology 208 (5): 354–359. doi:10.1016/j.ajog.2012.10.885. PMID 23123167. 
  16. ↑ "Consensus Statement on 21-Hydroxylase Deficiency from The European Society for Paediatric Endocrinology and The Lawson Wilkins Pediatric Endocrine Society". Hormone Research in Paediatrics 58 (4): 188–195. 2002. doi:10.1159/000065490. PMID 12324718. 
  17. ↑ Joint LWPES/ESPE CAH Working Group (September 2002). "Consensus Statement on 21-Hydroxylase Deficiency from The Lawson Wilkins Pediatric Endocrine Society and The European Society for Paediatric Endocrinology". The Journal of Clinical Endocrinology & Metabolism 87 (9): 4048–4053. doi:10.1210/jc.2002-020611. PMID 12213842. 



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