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