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21 Desoxycortisol (21DF) in congenital adrenal hyperplasia (CAH)

Pictogramme horloge Dr J-M. VANDERNOTTE & Pr J. FIET Pictogramme horloge July 2018

Content

  • Pathophysiology of CAH21
  • Consequences on plasma (or serum) concentrations of steroids in CAH21
  • Advantages of the 21DF assay (in addition to the 17OHP)

CAH are recessive, autosomal diseases due to a deficiency of several enzymes required for the synthesis of cortisol, aldosterone and adrenal androgens, and according to Figure 1.

21 hydroxylase (21OH) deficiency is the most common cause of CAH (95%) (CAH21).

CAH21 can be expressed in two forms:

  • a complete and congenital form with or without loss of salt at birth associated with sexual ambiguity in girls.
  • a partial and late onset form, which is much more common and most often expresses in childhood after puberty, associated in women with hirsutism, menstrual disorders, even lowered fertility.

Pathophysiology of CAH21

Figure 1: steroid metabolism during 21 hydroxylase deficiency of the adrenal cortex

All corticosteroids downstream of the deficiency are reduced (cortisol, aldosterone, DOC and corticosterone) except 21 DF, while all corticosteroids upstream are increased (170Hprogesterone, progesterone) because the reduction in cortisol stimulates the secretion of ACTH which activates the enzymes for steroid synthesis (except genetically deficient 21OH).

21Desoxycortisol (21DF) arises from the action of 11hydroxylase on 17OHprogesterone. This activity is minimal in normal subjects whilst in CAH21, the activity of 11 hydroxylase on the 17OHprogesterone is greatly increased. (Figure1).

Consequences on plasma (or serum) concentrations of steroids in CAH21

Plasma concentrations of 21F and 17OHprogesterone (17OHP) are highly elevated and correlated. They diagnose CAH21. In normal subjects – child, man or woman – plasma concentrations of 21 DF are <0.30 ng/mL while in CAH21 they can reach 50 ng/mL.

Table 1: Basal concentrations and 60 min after injection of Synacthene in normal, heterozygous subjects with 21 hydroxylase deficiency and patients with congenital adrenal hyperplasia (CAH) by means of late onset 21 hydroxylase deficiency.

In CAH21, the common increase in plasma concentrations of androgens (delta4-androstenedione then testosterone) arises from breakage of the lateral chain of 17OHP that has accumulated. These high plasma concentrations are responsible for the clinical hyperandrogenism of CAH21.

Moreover, the concentrations of mineralocorticoids including aldosterone can be reduced and are responsible for loss of salt (essentially in the congenital form).

In fact, plasma concentrations of 21DF and 17OHP in the full congenital form are higher than those found in the partial late onset form.

Assay of 21DF by Eurofins Biomnis in the plasma or serum is performed by RIA after extraction followed by chromatography. It is available in the form of a unitary test (Test code 21 DF)

Advantages of the 21 DF assay (in addition to the 17OHP)

  1. The 21DF increases the specificity of the 17OHP and makes a certain diagnosis of 21 hydroxylase deficiency. This is because the 21DF has a strictly adrenal origin unlike the 17OHP which has a mixed origin: adrenal and gonadal.
  2. In the term or premature infant, the 21 DF assay corrects temporary increases in 17 OHP which could incorrectly lead to a 21 hydroxylase deficiency. (Ref 1 and 2).
  3. The 21 DF enables screening for asymptomatic healthy carriers (but potential transmitters of 21 hydroxylase deficiency). The prevalence of the deficiency is important: 1/16 in the partial form, even more in certain populations. With this aim in mind: a Synacthene test needs to be performed (0.25 mg IV) with a 21 DF assay at 60 minutes. With a screening threshold of 0.55 ng/mL at 60 minutes, on 242 heterozygotes only 12 had a below threshold response. (Ref 3, 4, and 5).

Bibliography

1- Transient hyper-17-hydroxyprogesteronemia: a clinical subgroup of patients diagnosed at neonatal screening for congenital adrenal hyperplasia.
Cavarzere P, Samara-Boustani D, Flechtner I, Dechaux M, Elie C, Tardy V, Morel Y, Polak M.
Eur J Endocrinol. 2009 Aug;161(2):285-92.

2- A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia.
Fiet J, Le Bouc Y, Guéchot J, Hélin N, Maubert MA, Farabos D, Lamazière A.
J Endocr Soc. 2017 Feb 10;1(3):186-201.

3- Superior discriminating value of ACTH-stimulated serum 21-deoxycortisol in identifying heterozygote carriers for 21-hydroxylase deficiency.
Costa-Barbosa FA, Tonetto-Fernandes VF, Carvalho VM, Nakamura OH, Moura V, Bachega TA, Vieira JG, Kater CE.
Clin Endocrinol (Oxf). 2010 Dec;73(6):700-6.

4- Clinical and molecular characterization of a cohort of 161 unrelated women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency and 330 family members.
Bidet M, Bellanné-Chantelot C, Galand-Portier MB, Tardy V, Billaud L, Laborde K, Coussieu C, Morel Y, Vaury C, Golmard JL, Claustre A, Mornet E, Chakhtoura Z, Mowszowicz I, Bachelot A, Touraine P, Kuttenn F.
J Clin Endocrinol Metab. 2009 May;94(5):1570-8.

5- Comparison of basal and adrenocorticotropin-stimulated plasma 21-deoxycortisol and 17-hydroxyprogesterone values as biological markers of late-onset adrenal hyperplasia.
Fiet J, Gueux B, Gourmelen M, Kuttenn F, Vexiau P, Couillin P, Pham-Huu-Trung MT, Villette JM, Raux-Demay MC, Galons H, et al.
J Clin Endocrinol Metab. 1988 Apr;66(4):659-67

 


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