3 DISCUSSIONS
The 11βOH deficiency accounts for 5-8% of patients with
CAH.2 The patients are usually diagnosed before the
age of 13 years2–5 and mostly before the age of 4
years.3 Late diagnosis in adult aged 28-years and
above have been reported; however, it is rare.6–8
The 11βOH converts 11-desoxycortisol (11-DC) to cortisol and
11-deoxycorticosterone (DOC) to corticosterone.9 The
decreased cortisol secretion results in elevated adrenocorticotropic
hormone (ACTH) plasma level as well as an overproduction of steroid
precursors and androgens (see the adrenal steroidogenesis pathway
described in Figure 3). Androgen excess produces virilisation and
precocious pseudo-puberty. The mineralocorticoid effect of the elevated
DOC can lead to hypertension in up to two thirds of untreated
patients.10 Excessive ACTH production results in
hyperplasia of ACTH-sensitive tissues in adrenal glands and others sites
such as the testes, causing adrenal masses and testicular masses known
as testicular adrenal rest tumors (TARTs).11
The 11βOH deficiency occurs as a classic or non-classic phenotype,
depending on the degree of clinical severity and the percentage loss of
enzyme activity.3 Non-classic phenotype present no
abnormalities at birth and later can present mild virilisation,
peripheral precocious puberty, with premature adrenarche and penis
enlargement in boys, and hirsutism as well as menstrual irregularities
in girls.12 Patients with non-classic 11βOH deficiency
usually do not develop hypertension.6 Untreated
patients may present accelerated skeletal maturation, resulting in short
final stature.3 The clinical signs are usually more
evident in female patients than in males.
Engels et al. reported that the accumulated adrenal steroid precursors
in patients with CAH can activate the glucocorticoid receptor and
protect the patients against adrenal crisis.13 The
most potent glucocorticoid receptor activating steroid precursors are
11-beta-hydroxylated steroids - 11-DC and DOC.14,15This mechanism that could explain the late diagnosis present in several
rare cases described in the literature. The non-inclusion of measurement
of 11-DC in dry blood spots in neonatal screening programs, and the
presence of elevated 17OHP that may lead to the misdiagnosis of 21-OH
deficiency, are other two factors that can contribute to a delay in
diagnosis.
Arterial hypertension is another important feature of the classic form
of this deficiency. The exact pathophysiology of hypertension in 11βOH
deficiency remains unclear. Peter et al. discussed the predominant role
of the DOC with intrinsic mineralocorticoid activity as a possible
cause.15 However, the DOC levels do not correlate with
the severity of hypertension.6 Overall, the
hypertension in 11βOH deficiency is hyporeninemic, without overt
alterations in serum potassium and sodium
concentrations.16 Breil et al. reported several
cardiovascular conditions associated with 11βOH deficiency such as left
ventricular hypertrophy, ischemic heart disease, hypertensive
retinopathy, and cerebrovascular accidents2 and some
studies have demonstrated that the left ventricular hypertrophy in 11βOH
deficiency can be reversed after bilateral
adrenalectomy.17,18
The intra-testicular inclusions are present in approximately 42% of
cases of male patients with CAH.19 The tumor growth
increases the intra-testicular pressure and reduces blood flow causing
testicular damage with resulting oligo- or
azoospermia.2 Despite their benign character,
monitoring of TARTs is important as they are hardly distinguishable from
the Leydig-cell tumours (LCT). Bilateral tumours are more frequently
seen in TARTs with 83% of cases than LCT with only 2.5% of
cases.20 A testicular biopsy can always be performed
to help in the differential diagnosis. These inclusions are
ACTH-dependent benign tumors and can regress with ACTH suppression in
most cases.
The treatment modalities in 11βOH deficiency consists of glucocorticoid
suppressive therapy and surgical correction of the ambiguous external
genitalia in virilized female patients.17 The
glucocorticoids can substitute for the cortisol deficiency and inhibit
ACTH oversecretion, and thus suppress the excessive androgen and
mineralocorticoid production. However, in CAH, an effective suppression
of ACTH sometimes requires high doses of glucocorticoid over a prolonged
period of time,21 which explains the difficulty to
maintain a satisfactory adrenal suppression without producing an
unacceptable degree of hypercortisolism. The bilateral adrenalectomy was
proposed as an alternative; nevertheless, the patient compliance is
required for a lifelong hormonal substitution. Nasir et al. opted for it
in the management of a difficult case with failure to suppress androgen
production.22 Chabre et al. have applied it in a case
of a patient with severe hypertension who had experienced longterm
difficulties with equilibrium and compliance with the suppressive
therapy.17 Finally, Hinz et al. reported bilateral
adrenalectomy in a 15 year-old patient with resistant hypertension
despite good compliance.23